3-(phenoxyphenylmethyl)pyrrolidine compounds

ABSTRACT

In one aspect, the invention relates to compounds of formula I: 
                         
where a and R 1-6  are as defined in the specification, or a pharmaceutically acceptable salt thereof. The compounds of formula I are serotonin and norepinephrine reuptake inhibitors. In another aspect, the invention relates to pharmaceutical compositions comprising such compounds; methods of using such compounds; and process and intermediates for preparing such compounds.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application No.61/135,828, filed on Jul. 24, 2008; the entire disclosure of which isincorporated herein by reference in its entirety.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to 3-(phenoxyphenylmethyl)pyrrolidinecompounds having activity as serotonin (5-HT) and norepinephrine (NE)reuptake inhibitors. The invention also relates to pharmaceuticalcompositions comprising such compounds, processes and intermediates forpreparing such compounds and methods of using such compounds to treat apain disorder, such as neuropathic pain, and other ailments.

2. State of the Art

Pain is an unpleasant sensory and emotional experience associated withactual or potential tissue damage, or described in terms of such damage(International Association for the Study of Pain, Pain Terminology).Chronic pain persists beyond acute pain or beyond the expected time foran injury to heal (American Pain Society. “Pain Control in the PrimaryCare Setting.” 2006:15). Neuropathic pain is pain initiated or caused bya primary lesion or dysfunction in the nervous system. Peripheralneuropathic pain occurs when the lesion or dysfunction affects theperipheral nervous system and central neuropathic pain when the lesionor dysfunction affects the central nervous system (IASP).

Several types of therapeutic agents are currently used to treatneuropathic pain including, for example, tricyclic antidepressants(TCAs), serotonin and norepinephrine reuptake inhibitors (SNRIs),calcium channel ligands (e.g., gabapentin and pregabalin), topicallidocaine, and opioid agonists (e.g., morphine, oxycodone, methadone,levorphanol and tramadol). However, neuropathic pain can be verydifficult to treat with no more than 40-60% of patients achieving, atbest, partial relief of their pain (R. H. Dworkin et al. (2007) Pain132:237-251 at 247). Moreover, all of the therapeutic agents currentlyused to treat neuropathic pain have various side effects (e.g., nausea,sedation, dizziness and somnolence) that can limit their effectivenessin some patients (Dworkin et al. supra. at 241).

SNRIs, such as duloxetine and venlafaxine, are often used as first linetherapy for treating neuropathic pain. These agents inhibit the reuptakeof both serotonin (5-hydroxytrypamine, 5-HT) and norepinephrine (NE) bybinding to the serotonin and norepinephrine transporters (SERT and NET,respectively). However, both duloxetine and venlafaxine have higheraffinity for SERT relative to NET (Vaishnavi et al. (2004) Biol.Psychiatry 55(3):320-322).

Preclinical studies suggest that inhibition of both SERT and NET may benecessary for maximally effective treatment of neuropathic and otherchronic pain states (Jones et al. (2006) Neuropharmacology51(7-8):1172-1180; Vickers et al. (2008) Bioorg. Med. Chem. Lett.18:3230-3235; Fishbain et al. (2000) Pain Med. 1(4):310-316; andMochizucki (2004) Human Psychopharmacology 19:S15-S19). However, inclinical studies, the inhibition of SERT has been reported to be relatedto nausea and other side effects (Greist et al. (2004) Clin. Ther.26(9):1446-1455). Thus, therapeutic agents having more balanced SERT andNET affinity or slightly higher NET affinity are expected to beparticularly useful for treating chronic pain while producing fewer sideeffects, such as nausea.

Thus, a need exists for novel compounds that are useful for treatingchronic pain, such as neuropathic pain. In particular, a need exists fornovel compounds that are useful for treating chronic pain and that havereduced side effects, such as nausea.

A need also exists for novel dual-acting compounds that inhibit bothSERT and NET. In particular, a need exists for novel dual-actingcompounds that have high affinity for NET (e.g., pK_(i)≧8.0 or K_(i)≦10nM). Especially needed are novel dual-acting compounds that have highaffinity for NET and which also have a relatively balanced affinity forSERT relative to NET (e.g., a SERT/NET binding K_(i) ratio of 0.1 to100), or which have higher affinity for NET relative to SERT.

SUMMARY OF THE INVENTION

The present invention provides novel compounds that have been found topossess serotonin reuptake inhibitory activity and norepinephrinereuptake inhibitory activity. Accordingly, compounds of the inventionare expected to be useful and advantageous as therapeutic agents forthose diseases and disorders that can be treated by inhibition of theserotonin and/or norepinephrine transporter, such as neuropathic pain.

One aspect of the invention relates to a compound of formula I:

where:

a is 0 to 5;

each R¹ is independently selected from halo, —C₁₋₆alkyl, —C₂₋₆alkynyl,—O—C₁₋₆alkyl, —C₁₋₄alkylene-O—C₁₋₄alkyl, —C₀₋₁alkylene-phenyl,—O—C₀₋₃alkylene-phenyl, —C₀₋₆alkylene-OH, —CN, —C₀₋₂alkylene-COOH, —CHO,—C(O)—C₁₋₆alkyl, —C(O)O—C₁₋₄alkyl, —CH₂SH, —S—C₁₋₆alkyl,—C₁₋₄alkylene-S—C₁₋₄alkyl, —SO₂—C₁₋₆alkyl, —SO₂NR^(a)R^(b), —NHSO₂R^(a),—C₀₋₁alkylene-NR^(a)R^(b), —NHC(O)—C₁₋₆alkyl, —C(O)NR^(a)R^(b), and—NO₂;

R² through R⁶ are independently selected from H, halo, —C₁₋₆alkyl,—C₂₋₆alkynyl, —O—C₁₋₆alkyl, —C₁₋₄alkylene-O—C₁₋₄alkyl,—C₀₋₁alkylene-phenyl, —O—C₀₋₃alkylene-phenyl, —C₀₋₆alkylene-OH, —CN,—C₀₋₂alkylene-COOH, —CHO, —C(O)—C₁₋₆alkyl, —C(O)O—C₁₋₄alkyl, —CH₂SH,—S—C₁₋₆alkyl, —C₁₋₄alkylene-S—C₁₋₄alkyl, —SO₂—C₁₋₆alkyl,—SO₂NR^(a)R^(b), —NHSO₂R^(a), —C₀₋₁alkylene-NR^(a)R^(b),—NHC(O)—C₁₋₆alkyl, —C(O)NR^(a)R^(b), and —NO₂;

R^(a) and R^(b) are independently H or —C₁₋₄alkyl;

each alkyl in R¹ through R⁶ is optionally substituted with 1 to 5 fluoroatoms; and each phenyl in R¹ through R⁶ is optionally substituted with 1or 2 groups independently selected from halo, —C₁₋₆alkyl, and—O—C₁₋₆alkyl;

or a pharmaceutically acceptable salt thereof.

Another aspect of the invention relates to compounds of formula I havinga configuration selected from:

or enriched in a stereoisomeric form having such configuration.

Yet another aspect of the invention relates to pharmaceuticalcompositions comprising a pharmaceutically acceptable carrier and acompound of the invention. Such compositions may optionally containother active agents such as anti-Alzheimer's agents, anticonvulsants,antidepressants, anti-Parkinson's agents, dual serotonin-norepinephrinereuptake inhibitors, non-steroidal anti-inflammatory agents,norepinephrine reuptake inhibitors, opioid agonists, selective serotoninreuptake inhibitors, sodium channel blockers, sympatholytics, andcombinations thereof. Accordingly, in yet another aspect of theinvention, a pharmaceutical composition comprises a compound of theinvention, a second active agent, and a pharmaceutically acceptablecarrier. Another aspect of the invention relates to a combination ofactive agents, comprising a compound of the invention and a secondactive agent. The compound of the invention can be formulated togetheror separately from the additional agent(s). When formulated separately,a pharmaceutically acceptable carrier may be included with theadditional agent(s). Thus, yet another aspect of the invention relatesto a combination of pharmaceutical compositions, the combinationcomprising: a first pharmaceutical composition comprising a compound offormula I or a pharmaceutically acceptable salt thereof and a firstpharmaceutically acceptable carrier; and a second pharmaceuticalcomposition comprising a second active agent and a secondpharmaceutically acceptable carrier. The invention also relates to a kitcontaining such pharmaceutical compositions, for example where the firstand second pharmaceutical compositions are separate pharmaceuticalcompositions.

Compounds of the invention possess serotonin reuptake inhibitoryactivity and norepinephrine reuptake inhibitory activity, and aretherefore expected to be useful as therapeutic agents for treatingpatients suffering from a disease or disorder that is treated by theinhibition of the serotonin and/or the norepinephrine transporter. Thus,one aspect of the invention relates to a method of treating: a paindisorder such as neuropathic pain or fibromyalgia; a depressive disordersuch as major depression; an affective disorder such as an anxietydisorder; attention deficit hyperactivity disorder; a cognitive disordersuch as dementia; stress urinary incontinence; chronic fatigue syndrome;obesity; or vasomotor symptoms associated with menopause, comprisingadministering to a patient a therapeutically effective amount of acompound of the invention.

Still another aspect of the invention relates to a method for inhibitingserotonin reuptake in a mammal comprising administering to the mammal, aserotonin transporter-inhibiting amount of a compound of the invention.Yet another aspect of the invention relates to a method for inhibitingnorepinephrine reuptake in a mammal comprising administering to themammal, a norepinephrine transporter-inhibiting amount of a compound ofthe invention. And another aspect of the invention relates to a methodfor inhibiting serotonin reuptake and norepinephrine reuptake in amammal comprising administering to the mammal, a serotonin transporter-and norepinephrine transporter-inhibiting amount of a compound of theinvention.

Among the compounds of formula I, compounds of particular interest arethose having an inhibitory constant (pK_(i)) at SERT greater than orequal to 7.5 and an inhibitory constant (pK_(i)) at NET greater than orequal to 7.0. In another embodiment, compounds of interest have balancedSERT and NET activity, i.e., have the same pK_(i) value at both SERT andNET±0.5. Further compounds of particular interest are those having aserotonin reuptake inhibition IC₅₀ value of less than or equal to 100 nMand a norepinephrine reuptake inhibition IC₅₀ value of less than orequal to 100 nM.

Since compounds of the invention possess serotonin reuptake inhibitoryactivity and norepinephrine reuptake inhibitory activity, such compoundsare also useful as research tools. Accordingly, one aspect of theinvention relates to a method of using a compound of the invention as aresearch tool, comprising conducting a biological assay using a compoundof the invention. Compounds of the invention can also be used toevaluate new chemical compounds. Thus another aspect of the inventionrelates to a method of evaluating a test compound in a biological assay,comprising: (a) conducting a biological assay with a test compound toprovide a first assay value; (b) conducting the biological assay with acompound of the invention to provide a second assay value; wherein step(a) is conducted either before, after or concurrently with step (b); and(c) comparing the first assay value from step (a) with the second assayvalue from step (b). Exemplary biological assays include a serotoninreuptake assay and a norepinephrine reuptake assay. Still another aspectof the invention relates to a method of studying a biological system orsample comprising serotonin transporters, norepinephrine transporters,or both, the method comprising: (a) contacting the biological system orsample with a compound of the invention; and (b) determining the effectscaused by the compound on the biological system or sample.

The invention also relates to processes and intermediates useful forpreparing compounds of the invention. Accordingly, one aspect of theinvention relates to a process for preparing a compound of formula I,the process comprising deprotecting a compound of the formula:

where P is an amino-protecting group to provide a compound of formula I,or a salt thereof. In other aspects, the invention relates to novelintermediates used in such processes. In one aspect of the invention,such novel intermediates have the formula of compound 8 or compound 8′,as defined herein.

Another aspect of the invention relates to a process for preparingcompound 2 or compound 2′, which are intermediates useful for preparingcompounds of the invention, comprising reacting compound 1 or compound1′ with sodium hypochlorite in the presence of2,2,6,6-tetramethyl-1-piperidinyloxy, free radical (TEMPO) and potassiumbromide in water; where compounds 1, 1′, 2 and 2′ are as defined herein.

Yet another aspect of the invention relates to the use of compounds ofthe invention for the manufacture of medicaments, especially for themanufacture of medicaments useful for treating pain disorders,depressive disorders, affective disorders, attention deficithyperactivity disorder, cognitive disorders, stress urinaryincontinence, for inhibiting serotonin reuptake in a mammal, or forinhibiting norepinephrine reuptake in a mammal. Still another aspect ofthe invention relates to the use of compounds of the invention asresearch tools. Other aspects and embodiments of the invention aredisclosed herein.

BRIEF DESCRIPTION OF THE DRAWINGS

Various aspects of the present invention are illustrated by reference tothe accompanying drawings.

FIG. 1 shows a powder x-ray diffraction (PXRD) pattern of a crystallinemonohydrochloride salt of the compound of Example 11,(S)-3-[(R)-(2,6-dichloro-3,5-difluorophenoxy)phenylmethyl]pyrrolidine.

FIG. 2 shows a differential scanning calorimetry (DSC) trace and

FIG. 3 shows a thermal gravimetric analysis (TGA) trace for thiscrystalline salt.

FIG. 4 shows a powder x-ray diffraction (PXRD) pattern of a crystallinemonohydrochloride salt of the compound of Example 14,(R)-3-[(S)-(2-chloro-3,6-difluorophenoxy)phenyl-methyl]pyrrolidine.

FIG. 5 shows a differential scanning calorimetry (DSC) trace and

FIG. 6 shows a thermal gravimetric analysis (TGA) trace for thiscrystalline salt.

FIG. 7 shows a powder x-ray diffraction (PXRD) pattern of a crystallinemonohydrochloride salt of the compound of Example 16,(R)-3-[(S)-(3,5-dichlorophenoxy)phenylmethyl]pyrrolidine.

FIG. 8 shows a differential scanning calorimetry (DSC) trace and athermal gravimetric analysis (TGA) trace for this crystalline salt.

DETAILED DESCRIPTION OF THE INVENTION Definitions

When describing the compounds, compositions, methods and processes ofthe invention, the following terms have the following meanings unlessotherwise indicated. Additionally, as used herein, the singular forms“a,” “an” and “the” include the corresponding plural forms unless thecontext of use clearly dictates otherwise. The terms “comprising”,“including,” and “having” are intended to be inclusive and mean thatthere may be additional elements other than the listed elements. Allnumbers expressing quantities of ingredients, properties such asmolecular weight, reaction conditions, and so forth used herein are tobe understood as being modified in all instances by the term “about,”unless otherwise indicated. Accordingly, the numbers set forth hereinare approximations that may vary depending upon the desired propertiessought to be obtained by the present invention. At least, and not as anattempt to limit the application of the doctrine of equivalents to thescope of the claims, each number should at least be construed in lightof the reported significant digits and by applying ordinary roundingtechniques.

The term “alkyl” means a monovalent saturated hydrocarbon group whichmay be linear or branched. Unless otherwise defined, such alkyl groupstypically contain from 1 to 10 carbon atoms and include, for example,—C₁₋₂alkyl, —C₁₋₃alkyl, —C₁₋₄alkyl, —C₁₋₆alkyl, and —C₁₋₈alkyl.Representative alkyl groups include, by way of example, methyl, ethyl,n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl,n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl and the like.

When a specific number of carbon atoms is intended for a particular termused herein, the number of carbon atoms is shown preceding the term assubscript. For example, the term “—C₁₋₆alkyl” means an alkyl grouphaving from 1 to 6 carbon atoms, and the term “—C₁₋₄alkylene” means analkylene group having from 1 to 4 carbon atoms, where the carbon atomsare in any acceptable configuration.

The term “alkylene” means a divalent saturated hydrocarbon group thatmay be linear or branched. Unless otherwise defined, such alkylenegroups typically contain from 0 to 10 carbon atoms and include, forexample, —C₀₋₁alkylene, —C₀₋₂alkylene, —C₀₋₃alkylene, —C₀₋₆alkylene,—C₁₋₄alkylene, —C₂₋₄alkylene and —C₁₋₆alkylene. Representative alkylenegroups include, by way of example, methylene, ethane-1,2-diyl(“ethylene”), propane-1,2-diyl, propane-1,3-diyl, butane-1,4-diyl,pentane-1,5-diyl and the like. It is understood that when the alkyleneterm includes zero carbons such as —C₀₋₁alkylene-, —C₀₋₃alkylene- or—C₀₋₆alkylene-, such terms are intended to include the absence of carbonatoms, i.e., the alkylene group is not present except for a covalentbond attaching the groups separated by the alkylene term.

The term “alkynyl” means a monovalent unsaturated hydrocarbon groupwhich may be linear or branched and which has at least one, andtypically 1, 2 or 3, carbon-carbon triple bonds. Unless otherwisedefined, such alkynyl groups typically contain from 2 to 10 carbon atomsand include, for example, —C₂₋₄alkynyl, —C₂₋₆alkynyl and —C₃₋₁₀alkynyl.Representative alkynyl groups include, by way of example, ethynyl,n-propynyl, n-but-2-ynyl, n-hex-3-ynyl and the like.

The term “halo” means fluoro, chloro, bromo and iodo.

The term “pharmaceutically acceptable” refers to a material that is notbiologically or otherwise unacceptable when used in the invention. Forexample, the term “pharmaceutically acceptable carrier” refers to amaterial that can be incorporated into a composition and administered toa patient without causing unacceptable biological effects or interactingin an unacceptable manner with other components of the composition. Suchpharmaceutically acceptable materials typically have met the requiredstandards of toxicological and manufacturing testing, and include thosematerials identified as suitable inactive ingredients by the U.S. Foodand Drug Administration.

The term “pharmaceutically acceptable salt” means a salt prepared from abase or an acid which is acceptable for administration to a patient,such as a mammal (e.g., salts having acceptable mammalian safety for agiven dosage regime). However, it is understood that the salts coveredby the invention are not required to be pharmaceutically acceptablesalts, such as salts of intermediate compounds that are not intended foradministration to a patient. Pharmaceutically acceptable salts can bederived from pharmaceutically acceptable inorganic or organic bases andfrom pharmaceutically acceptable inorganic or organic acids. Inaddition, when a compound of formula I contains both a basic moiety,such as an amine, and an acidic moiety such as a carboxylic acid,zwitterions may be formed and are included within the term “salt” asused herein. Salts derived from pharmaceutically acceptable inorganicbases include ammonium, calcium, copper, ferric, ferrous, lithium,magnesium, manganic, manganous, potassium, sodium, and zinc salts, andthe like. Salts derived from pharmaceutically acceptable organic basesinclude salts of primary, secondary and tertiary amines, includingsubstituted amines, cyclic amines, naturally-occurring amines and thelike, such as arginine, betaine, caffeine, choline,N,N′-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol,2-dimethylaminoethanol, ethanolamine, ethylenediamine,N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine,hydrabamine, isopropylamine, lysine, methylglucamine, morpholine,piperazine, piperadine, polyamine resins, procaine, purines,theobromine, triethylamine, trimethylamine, tripropylamine, tromethamineand the like. Salts derived from pharmaceutically acceptable inorganicacids include salts of boric, carbonic, hydrohalic (hydrobromic,hydrochloric, hydrofluoric or hydroiodic), nitric, phosphoric, sulfamicand sulfuric acids. Salts derived from pharmaceutically acceptableorganic acids include salts of aliphatic hydroxyl acids (e.g., citric,gluconic, glycolic, lactic, lactobionic, malic, and tartaric acids),aliphatic monocarboxylic acids (e.g., acetic, butyric, formic, propionicand trifluoroacetic acids), amino acids (e.g., aspartic and glutamicacids), aromatic carboxylic acids (e.g., benzoic, p-chlorobenzoic,diphenylacetic, gentisic, hippuric, and triphenylacetic acids), aromatichydroxyl acids (e.g., o-hydroxybenzoic, p-hydroxybenzoic,1-hydroxynaphthalene-2-carboxylic and 3-hydroxynaphthalene-2-carboxylicacids), ascorbic, dicarboxylic acids (e.g., fumaric, maleic, oxalic andsuccinic acids), glucoronic, mandelic, mucic, nicotinic, orotic, pamoic,pantothenic, sulfonic acids (e.g., benzenesulfonic, camphosulfonic,edisylic, ethanesulfonic, isethionic, methanesulfonic,naphthalenesulfonic, naphthalene-1,5-disulfonic,naphthalene-2,6-disulfonic and p-toluenesulfonic acids), xinafoic acid,and the like.

The term “solvate” means a complex or aggregate formed by one or moremolecules of a solute, e.g., a compound of formula I or apharmaceutically acceptable salt thereof, and one or more molecules of asolvent. Such solvates are typically crystalline solids having asubstantially fixed molar ratio of solute and solvent. Representativesolvents include, by way of example, water, methanol, ethanol,isopropanol, acetic acid and the like. When the solvent is water, thesolvate formed is a hydrate.

The term “therapeutically effective amount” means an amount sufficientto effect treatment when administered to a patient in need thereof,i.e., the amount of drug needed to obtain the desired therapeuticeffect. For example, a therapeutically effective amount for treatingneuropathic pain is an amount of compound needed to, for example,reduce, suppress, eliminate or prevent the symptoms of neuropathic painor to treat the underlying cause of neuropathic pain. On the other hand,the term “effective amount” means an amount sufficient to obtain adesired result, which may not necessary be a therapeutic result. Forexample, when studying a system comprising a norepinephrine transporter,an “effective amount” may be the amount needed to inhibit norepinephrinereuptake.

The term “treating” or “treatment” as used herein means the treating ortreatment of a disease or medical condition (such as neuropathic pain)in a patient, such as a mammal (particularly a human), that includes:(a) preventing the disease or medical condition from occurring, i.e.,prophylactic treatment of a patient; (b) ameliorating the disease ormedical condition, i.e., eliminating or causing regression of thedisease or medical condition in a patient; (c) suppressing the diseaseor medical condition, i.e., slowing or arresting the development of thedisease or medical condition in a patient; or (d) alleviating thesymptoms of the disease or medical condition in a patient. For example,the term “treating neuropathic pain” would include preventingneuropathic pain from occurring, ameliorating neuropathic pain,suppressing neuropathic pain, and alleviating the symptoms ofneuropathic pain. The term “patient” is intended to include thosemammals, such as humans, that are in need of treatment or diseaseprevention, that are presently being treated for disease prevention ortreatment of a specific disease or medical condition, as well as testsubjects in which compounds of the invention are being evaluated orbeing used in a assay, for example an animal model.

All other terms used herein are intended to have their ordinary meaningas understood by those of ordinary skill in the art to which theypertain.

In one aspect, this invention relates to novel compounds of formula I:

or a pharmaceutically acceptable salt thereof.

As used herein, the term “compound of the invention” includes allcompounds encompassed by formula I such as the species embodied informula Ia-Id, II-XXI, II′-XXI′ and all other subspecies of suchformulas. In addition, when the compound of the invention contain abasic or acidic group (e.g., amino or carboxyl groups), the compound canexist as a free base, free acid, or in various salt forms. All such saltforms are included within the scope of the invention. Accordingly, thoseskilled in the art will recognize that reference to a compound herein,for example, reference to a “compound of the invention” or a “compoundof formula I” includes a compound of formula I as well aspharmaceutically acceptable salts of that compound unless otherwiseindicated. Furthermore, solvates of compounds of formula I are includedwithin the scope of this invention.

The compounds of formula I contain at least two chiral centers andtherefore, these compounds may be prepared and used in variousstereoisomeric forms. Accordingly, the invention also relates to racemicmixtures, pure stereoisomers (e.g., enantiomers and diastereoisomers),stereoisomer-enriched mixtures, and the like unless otherwise indicated.When a chemical structure is depicted herein without anystereochemistry, it is understood that all possible stereoisomers areencompassed by such structure. Thus, for example, the terms “compound offormula I,” “compounds of formula II,” and so forth, are intended toinclude all possible stereoisomers of the compound. Similarly, when aparticular stereoisomer is shown or named herein, it will be understoodby those skilled in the art that minor amounts of other stereoisomersmay be present in the compositions of the invention unless otherwiseindicated, provided that the utility of the composition as a whole isnot eliminated by the presence of such other isomers. Individualenantiomers may be obtained by numerous methods that are well known inthe art, including chiral chromatography using a suitable chiralstationary phase or support, or by chemically converting them intodiastereoisomers, separating the diastereoisomers by conventional meanssuch as chromatography or recrystallization, then regenerating theoriginal enantiomers. Additionally, where applicable, all cis-trans orE/Z isomers (geometric isomers), tautomeric forms and topoisomeric formsof the compounds of the invention are included within the scope of theinvention unless otherwise specified.

More specifically, compounds of formula I contain at least two chiralcenters indicated by the symbols * and ** in the following formula:

In one stereoisomer, both carbon atoms identified by the * and **symbols have the (R) configuration. This embodiment of the invention isshown in formula Ia:

In this embodiment, compounds have the (R,R) configuration at the * and** carbon atoms or are enriched in a stereoisomeric form having the(R,R) configuration at these carbon atoms.

In another stereoisomer, both carbon atoms identified by the * and **symbols have the (S) configuration. This embodiment of the invention isshown in formula Ib:

In this embodiment, compounds have the (S,S) configuration at the * and** carbon atoms or are enriched in a stereoisomeric form having the(S,S) configuration at these carbon atoms.

In yet another stereoisomer, the carbon atom identified by the symbol *has the (S) configuration and the carbon atom identified by the symbol** has the (R) configuration. This embodiment of the invention is shownin formula Ic:

In this embodiment, compounds have the (S,R) configuration at the * and** carbon atoms or are enriched in a stereoisomeric form having the(S,R) configuration at these carbon atoms.

In still another stereoisomer, the carbon atom identified by thesymbol * has the (R) configuration and the carbon atom identified by thesymbol ** has the (S) configuration. This embodiment of the invention isshown in formula Id:

In this embodiment, compounds have the (R,S) configuration at the * and** carbon atoms or are enriched in a stereoisomeric form having the(R,S) configuration at these carbon atoms.

Compounds of formula Ia and Ib are enantiomers and therefore, inseparate aspects, this invention relates to each individual enantiomer(i.e., Ia or Ib), a racemic mixture of Ia and Ib, or anenantiomer-enriched mixture of Ia and Ib comprising predominantly Ia orpredominantly Ib. Similarly, compounds of formula Ic and Id areenantiomers and therefore, in separate aspects, this invention relatesto each individual enantiomer (i.e., Ic or Id), a racemic mixture of Icand Id, or a enantiomer-enriched mixture of Ic and Id comprisingpredominantly Ic or predominantly Id.

In some embodiments, in order to optimize the therapeutic activity ofthe compounds of the invention, e.g., to treat neuropathic pain, it maybe desirable that the carbon atoms identified by the * and ** symbolshave a particular (R,R), (S,S), (S,R), or (R,S) configuration or areenriched in a stereoisomeric form having such configuration. Forexample, in one embodiment, the compounds of the invention have the(S,R) configuration of formula Ic or are enriched in a stereoisomericform having the (S,R) configuration, and in another embodiment, thecompounds of the invention have the (R,S) configuration of formula Id,or are enriched in a stereoisomeric form having the (R,S) configuration.In other embodiments, the compounds of the invention are present asracemic mixtures, for example as a mixture of enantiomers of formula Iaand Ib, or as a mixture of enantiomers of formula Ic and Id.

The compounds of the invention, as well as those compounds used in theirsynthesis, may also include isotopically-labeled compounds, i.e., whereone or more atoms have been enriched with atoms having an atomic massdifferent from the atomic mass predominantly found in nature. Examplesof isotopes that may be incorporated into the compounds of formula I,for example, include, but are not limited to, ²H, ³H, ¹³C, ¹⁴C, ¹⁵N,¹⁸O, ¹⁷O, ³⁵S, ³⁶Cl, and ¹⁸F. Of particular interest are compounds offormula I enriched in tritium or carbon-14 which can be used, forexample, in tissue distribution studies; compounds of formula I enrichedin deuterium especially at a site of metabolism resulting, for example,in compounds having greater metabolic stability; and compounds offormula I enriched in a positron emitting isotope, such as ¹¹C, ¹⁸F, ¹⁵Oand ¹³N, which can be used, for example, in Positron Emission Topography(PET) studies.

The compounds of the invention have been found to possess serotoninreuptake inhibitory activity and norepinephrine reuptake inhibitoryactivity. Among other properties, such compounds are expected to beuseful as therapeutic agents for treating chronic pain, such asneuropathic pain. By combining dual activity into a single compound,double therapy can be achieved, i.e., serotonin reuptake inhibitoryactivity and norepinephrine reuptake inhibitory activity, using a singleactive component. Since pharmaceutical compositions containing oneactive component are typically easier to formulate than compositionscontaining two active components, such single-component compositionsprovide a significant advantage over compositions containing two activecomponents.

Many combined serotonin and norepinephrine reuptake inhibitors (SNRIs)are more selective for SERT than for NET. For example, milnacipran,duloxetine, and venlafaxine and exhibit 2.5-fold, 10-fold, and 100-foldselectivity (measured as pK_(i)) for SERT over NET, respectively. Some,however, are less selective, such as bicifadine, which has a pK_(i) atSERT of 7.0 and a pK_(i) at NET of 6.7. Since it may be desirable toavoid selective compounds, in one embodiment of the invention thecompounds have a more balanced SERT and NET activity, i.e., have thesame pK_(i) value at both SERT and NET±0.5.

The nomenclature used herein to name the compounds of the invention isillustrated in the Examples herein. This nomenclature has been derivedusing the commercially-available AutoNom software (MDL, San Leandro,Calif.). Typically, compounds of formula I, have been named as3-(phenoxyphenylmethyl)pyrrolidines.

Representative Embodiments

The following substituents and values are intended to providerepresentative examples of various aspects and embodiments of theinvention. These representative values are intended to further defineand illustrate such aspects and embodiments and are not intended toexclude other embodiments or to limit the scope of the invention. Inthis regard, the representation that a particular value or substituentis preferred is not intended in any way to exclude other values orsubstituents from the invention unless specifically indicated.

In one aspect, this invention relates to compounds of formula I:

The integer a can be 0, 1, 2, 3, 4 or 5. In one particular embodiment, ais 0, 1 or 2.

Each R¹ is independently selected from halo, —C₁₋₆alkyl, —C₂₋₆alkynyl,—O—C₁₋₆alkyl, —C₁₋₄alkylene-O—C₁₋₄alkyl, —C₀₋₁alkylene-phenyl,—O—C₀₋₃alkylene-phenyl, —C₀₋₆alkylene-OH, —CN, —C₀₋₂alkylene-COOH, —CHO,—C(O)—C₁₋₆alkyl, —C(O)O—C₁₋₄alkyl, —CH₂SH, —S—C₁₋₆alkyl,—C₁₋₄alkylene-S—C₁₋₄alkyl, —SO₂—C₁₋₆alkyl, —SO₂NR^(a)R^(b), —NHSO₂R^(a),—C₀₋₁alkylene-NR^(a)R^(b), —NHC(O)—C₁₋₆alkyl, —C(O)NR^(a)R^(b), and—NO₂. Further, each alkyl group in R¹ is optionally substituted with 1to 5 fluoro atoms. In addition, each phenyl group in R¹ may besubstituted with 1 or 2 groups independently selected from halo,—C₁₋₆alkyl, and —O—C₁₋₆alkyl.

R² through R⁶ are independently selected from H, halo, —C₁₋₆alkyl,—C₂₋₆alkynyl, —O—C₁₋₆alkyl, —C₁₋₄alkylene-O—C₁₋₄alkyl,—C₀₋₁alkylene-phenyl, —O—C₀₋₃alkylene-phenyl, —C₀₋₆alkylene-OH, —CN,—C₀₋₂alkylene-COOH, —CHO, —C(O)—C₁₋₆alkyl, —C(O)O—C₁₋₄alkyl, —CH₂SH,—S—C₁₋₆alkyl, —C₁₋₄alkylene-S—C₁₋₄alkyl, —SO₂—C₁₋₆alkyl,—SO₂NR^(a)R^(b), —NHSO₂R^(a), —C₀₋₁alkylene-NR^(a)R^(b),—NHC(O)—C₁₋₆alkyl, —C(O)NR^(a)R^(b), and —NO₂. Further, each alkyl groupin R² through R⁶ may be substituted with 1 to 5 fluoro atoms. Inaddition, each phenyl group in R² through R⁶ may be substituted with 1or 2 groups independently selected from halo, —C₁₋₆alkyl, and—O—C₁₋₆alkyl.

The R^(a) and R^(b) groups are independently H or —C₁₋₄alkyl. It isunderstood that when referring to “each alkyl” group in R¹ or in R²⁻⁶,the term also includes any alkyl groups that might be present in theR^(a) and R^(b) moieties.

In some embodiments of the invention, one or more positions on the arylring are substituted with a non-hydrogen moiety. For example, one suchembodiment may be described by stating that that “R² is a non-hydrogenmoiety”. It is understood that this means that R² can be any of thenon-hydrogen moieties defined in formula I, i.e., halo, —C₁₋₆alkyl,—C₂₋₆alkynyl, —O—C₁₋₆alkyl, —C₁₋₄alkylene-O—C₁₋₄alkyl,—C₀₋₁alkylene-phenyl, —O—C₀₋₃alkylene-phenyl, —C₀₋₆alkylene-OH, —CN,—C₀₋₂alkylene-COOH, —CHO, —C(O)—C₁₋₆alkyl, —C(O)O—C₁₋₄alkyl, —CH₂SH,—S—C₁₋₆alkyl, —C₁₋₄alkylene-S—C₁₋₄alkyl, —SO₂—C₁₋₆alkyl,—SO₂NR^(a)R^(b), —NHSO₂R^(a), —C₀₋₁alkylene-NR^(a)R^(b),—NHC(O)—C₁₋₆alkyl, —C(O)NR^(a)R^(b), and —NO₂.

Exemplary halo groups include fluoro, chloro, bromo, and iodo. Exemplary—C₁₋₆alkyl groups include —CH₃, —CH₂CH₃, and —CH(CH₃)₂, as well asfluoro-substituted —C₁₋₆alkyl groups such as —CF₃. Exemplary—C₂₋₆alkynyl groups include —CH═CH₂. Exemplary —O—C₁₋₆alkyl groupsinclude —OCH₃, —O—CH₂CH₃, and —OCH(CH₃)₂, as well a fluoro-substituted—O—C₁₋₆alkyl groups such as —OCF₃. Exemplary —C₁₋₄alkylene-O—C₁₋₄alkylgroups include —CH₂—OCH₃ and —CH₂—OCH₂CH₃. Exemplary—C₀₋₁alkylene-phenyl groups include phenyl and benzyl. Exemplary—O—C₀₋₃alkylene-phenyl groups include —O-phenyl and —O-benzyl. As notedabove, each phenyl group in R¹ and R² through R⁶ may be substituted with1 or 2 groups independently selected from halo, —C₁₋₆alkyl, and—O—C₁₋₆alkyl. Examples of such substituted —O—C₀₋₃alkylene-phenyl groupsinclude —O-2,4-dichlorophenyl, —O-3-chlorophenyl, —O-3-ethylphenyl,—O-4-ethylphenyl, —O-2-ethoxyphenyl, and —O-4-ethoxyphenyl. Exemplary—C₀₋₆alkylene-OH groups include —OH and —CH₂OH. Exemplary—C₀₋₂alkylene-COOH groups include —COOH. Exemplary —C(O)—C₁₋₆alkylgroups include —C(O)CH₃ and —C(O)CH₂CH₃. Exemplary —C(O)O—C₁₋₄alkylgroups include —C(O)OCH₃, —C(O)OCH₂CH₃, and —C(O)OCH(CH₃)₂. Exemplary—S—C₁₋₆alkyl groups include —SCH₃. Exemplary —C₁₋₄alkylene-S—C₁₋₄alkylgroups include —CH₂—S—CH₃. Exemplary —SO₂—C₁₋₆alkyl groups include—SO₂CH₃. Exemplary —SO₂NR^(a)R^(b) groups include —SO₂NH₂ and—SO₂N(CH₃)₂. Exemplary —NHSO₂R^(a) groups include —NHSO₂H and —NHSO₂CH₃.Exemplary —C₀₋₁alkylene-NR^(a)R^(b) groups include —NH₂, —N(CH₃)₂,—CH₂NH(CH₂CH₃), and —CH₂N(CH₃)(CH₂CH₃). Exemplary —NHC(O)—C₁₋₆alkylgroups include —NHC(O)CH₃ and —NHC(O)CH₂CH₃. Exemplary —C(O)NR^(a)R^(b)groups include —CONH₂, —CONH(CH₂CH₃), and —C(O)N(CH₃)CH₂CH₃.

In one embodiment, a is 1, and R¹ is halo, —C₁₋₆alkyl, —O—C₁₋₆alkyloptionally substituted with 1 to 5 fluoro atoms, —C₀₋₆alkylene-OH, —CN,—C₀₋₂alkylene-COOH, —CHO, —C(O)O—C₁₋₄alkyl or —C(O)NR^(a)R^(b). In oneparticular embodiment, the R¹ group is at the 2 or 3 position. Inanother embodiment, a is 2, and each R¹ is independently halo,—C₁₋₆alkyl optionally substituted with 1 to 5 fluoro atoms, or—SO₂—C₁₋₆alkyl. In another embodiment, a is 2, one R¹ group is halo, andthe other R¹ group is halo, —C₁₋₆alkyl optionally substituted with 1 to5 fluoro atoms, or —SO₂—C₁₋₆alkyl. In one particular embodiment, the R¹groups are at the 3 and 5 positions.

In one embodiment, R² is: H; halo; —C₁₋₆alkyl optionally substitutedwith 1 to 3 fluoro atoms; —O—C₁₋₆alkyl optionally substituted with 1 to3 fluoro atoms; —C₀₋₁alkylene-phenyl optionally substituted with 1 to 2halo atoms; —O—C₀₋₃alkylene-phenyl; —C₀₋₆alkylene-OH; —CN;—C(O)—C₁₋₆alkyl; —C(O)O—C₁₋₄alkyl; —S—C₁₋₆alkyl; —SO₂—C₁₋₆alkyl; or—NO₂.

In one embodiment, R³ is: H; halo; —C₁₋₆alkyl optionally substitutedwith 1 to 3 fluoro atoms; —O—C₁₋₆alkyl optionally substituted with 1 to3 fluoro atoms; —O—C₀₋₃alkylene-phenyl optionally substituted with 1halo, —C₁₋₆alkyl, or —O—C₁₋₆alkyl group; or —NO₂.

In one embodiment, R⁴ is: H; halo; —C₁₋₆alkyl optionally substitutedwith 1 to 5 fluoro atoms; —O—C₁₋₆alkyl optionally substituted with 1 to5 fluoro atoms; —C₀₋₁alkylene-phenyl; —O—C₀₋₃alkylene-phenyl;—SO₂—C₁₋₆alkyl; —C(O)NH₂; or —NO₂.

In one embodiment, R⁵ is H, halo, or —C₁₋₆alkyl.

In one embodiment, R⁶ is H, halo, —C₁₋₆alkyl, or —O—C₁₋₆alkyl.

In one embodiment, R² through R⁶ are H. In one particular embodiment, ais 0, which can be depicted as formula II:

In another particular embodiment, a is 1 to 5, and R¹ is as defined forformula I, which can be depicted as formula II′:

In one particular embodiment, a is 1 and R¹ is halo, —C₁₋₆alkyl,—O—C₁₋₆alkyl, —C₀₋₆alkylene-OH, or —CHO. In another embodiment, R¹ is2-F, 3-Cl, 3-CH₃, 3-OCH₃, 3-OCF₃, 3-CH₂OH, or 3-CHO. In yet anotherembodiment, R¹ is 3-CHO.

In another embodiment, R² is a non-hydrogen moiety as defined forformula I, and R³ through R⁶ are H. In one particular embodiment, a is0, which can be depicted as formula III:

In one particular embodiment, R² is halo, —C₁₋₆alkyl, —O—C₁₋₆alkyl,—C₀₋₁alkylene-phenyl, —O—C₀₋₃alkylene-phenyl, —C₀₋₆alkylene-OH,—C(O)—C₁₋₆alkyl, —C(O)O—C₁₋₄alkyl, —S—C₁₋₆alkyl, —SO₂—C₁₋₆alkyl, or—NO₂; where each alkyl is optionally substituted with 1 to 5 fluoroatoms, and each phenyl is optionally substituted with 1 or 2 groupsindependently selected from halo. In yet another embodiment, R² is F,Cl, Br, I, —CH₃, —CH₂CH₃, —CH(CH₃)₂, —CF₃, —OCH₃, —O—CH₂CH₃, —OCH(CH₃)₂,—OCF₃, -phenyl, —CH₂-phenyl, —O-benzyl, —C(O)CH₃, —C(O)CH₂CH₃, or —NO₂.In still another embodiment, R² is F, Cl, Br, —CH₂CH₃, —CH(CH₃)₂, —CF₃,—OCH(CH₃)₂, —OCF₃, —CH₂-phenyl, or —O-benzyl. In another particularembodiment, a is 1 to 5, and R¹ is as defined for formula I, which canbe depicted as formula III′:

In one particular embodiment, a is 1 or 2; R¹ is halo, —C₁₋₆alkyloptionally substituted with 1 to 5 fluoro atoms, —O—C₁₋₆alkyl optionallysubstituted with 1 to 5 fluoro atoms, —C₀₋₆alkylene-OH, —CN,—SO₂—C₁₋₆alkyl, or —C(O)NR^(a)R^(b); R² is halo, —C₁₋₆alkyl,—O—C₁₋₆alkyl, or —C₀₋₁alkylene-phenyl. In other embodiments: R² is halo,a is 1, and R¹ is halo, —C₁₋₆alkyl optionally substituted with 1 to 5fluoro atoms, or —O—C₁₋₆alkyl optionally substituted with 1 to 5 fluoroatoms; or R² is —C₁₋₆alkyl, a is 1, and R¹ is halo or —O—C₁₋₆alkyloptionally substituted with 1 to 5 fluoro atoms; or R² is —O—C₁₋₆alkyl,a is 1 or 2, and each R¹ is independently halo, —C₁₋₆alkyl optionallysubstituted with 1 to 5 fluoro atoms, —O—C₁₋₆alkyl optionallysubstituted with 1 to 5 fluoro atoms, —C₀₋₆alkylene-OH, —CN,—SO₂—C₁₋₆alkyl, or —C(O)NR^(a)R^(b); or R² is —C₀₋₁alkylene-phenyl, a is2, and each R¹ is independently halo. In other embodiments: R² is halo,a is 1, and R¹ is halo, —C₁₋₆alkyl, or —O—C₁₋₆alkyl; or R² is—C₁₋₆alkyl, a is 1, and R¹ is halo or —O—C₁₋₆alkyl; or R² is—O—C₁₋₆alkyl, a is 1 or 2, and each R¹ is independently halo,—C₁₋₆alkyl, —O—C₁₋₆alkyl optionally substituted with 1 to 5 fluoroatoms, —C₀₋₆alkylene-OH, —CN, or —CONH₂. In additional embodiments: R²is Cl, a is 1, and R¹ is 2-Cl, 3-Cl, 3-F, 3-CH₃, or 3-OCH₃; or R² is—CH(CH₃)₂, a is 1, and R¹ is 3-Cl, 3-F, or 3-OCH₃; or R² is —OCH₃, a is1, and R¹ is 2-Cl, 3-Cl, 3-F, 4-Cl, 2-OCF₃, 3-CH₂OH, 3-CN, 3-CONH₂, or4-CN; or R² is —OCH₃, a is 2, one R¹ is 3-F and the other R¹ is 5-F,5-Cl, or 5-CH₃.

In another embodiment, R³ is a non-hydrogen moiety as defined forformula I, and R² and R⁴ through R⁶ are H. In one particular embodiment,a is 0, which can be depicted as formula IV:

In one particular embodiment, R³ is: halo; —C₁₋₆alkyl optionallysubstituted with 1 to 5 fluoro atoms; —O—C₁₋₆alkyl optionallysubstituted with 1 to 5 fluoro atoms; —O—C₀₋₃alkylene-phenyl optionallysubstituted with a halo, —C₁₋₆alkyl, or —O—C₁₋₆alkyl group; or —NO₂. Inanother embodiment, the —O—C₀₋₃alkylene-phenyl group is optionallysubstituted with 3-Cl, 3-ethyl, 4-ethyl, 2-ethoxy, or 4-ethoxy. In yetanother embodiment, R³ is: halo; —C₁₋₆alkyl; or —O-phenyl optionallysubstituted with a halo group. In another embodiment, R³ is: F; Cl; Br;I; —CH₃; or —O-phenyl optionally substituted with 3-Cl, 4-F, or 4-Cl. Inyet another embodiment, R³ is F. In another embodiment, a is 1 to 5, andR¹ is as defined for formula I, which can be depicted as formula IV′:

In one particular embodiment, R³ is halo; a is 1 and R¹ is halo,—C₁₋₆alkyl, or —O—C₁₋₆alkyl optionally substituted with 1 to 5 fluoroatoms; or a is 2 and R¹ is independently halo or —SO₂—C₁₋₆alkyl. Inother embodiments: R³ is Cl, a is 1, and R¹ is 3-Cl, 2-F, 3-F, 2-CH₃,3-CH₃, 3-OCH₃, or 3-OCF₃; or R³ is F, a is 2, one R¹ is 3-SO₂CH₃ and theother R¹ is 5-F. In yet another embodiment, R³ is Cl and R¹ is 3-Cl or3-F.

In another embodiment, R⁴ is a non-hydrogen moiety as defined forformula I, and R², R³, R⁵, and R⁶ are H. In one particular embodiment, ais 0, which can be depicted as formula V:

In one particular embodiment, R⁴ is: halo; —C₁₋₆alkyl optionallysubstituted with 1 to 5 fluoro atoms; —O—C₁₋₆alkyl optionallysubstituted with 1 to 5 fluoro atoms; —C₀₋₁alkylene-phenyl;—O—C₀₋₃alkylene-phenyl; —SO₂—C₁₋₆alkyl; or —C(O)NR^(a)R^(b). In yetanother embodiment, R⁴ is —Cl, —CH₃, or —O-benzyl. In anotherembodiment, a is 1 to 5, and R¹ is as defined for formula I, which canbe depicted as formula V′:

In one particular embodiment, R⁴ is halo; a is 1; and R¹ is halo,—C₁₋₆alkyl, or —O—C₁₋₆alkyl optionally substituted with 1 to 5 fluoroatoms.

In another embodiment, R² and R³ are non-hydrogen moieties as definedfor formula I, and R⁴ through R⁶ are H. In one particular embodiment, ais 0, which can be depicted as formula VI:

In one particular embodiment, R² is halo, —C₁₋₆alkyl, —O—C₁₋₆alkyl, —CN,—C(O)—C₁₋₆alkyl, or —C(O)O—C₁₋₄alkyl; and R³ is halo, —C₁₋₆alkyloptionally substituted with 1 to 5 fluoro atoms, —O—C₁₋₆alkyl, or—O—C₀₋₃alkylene-phenyl. In other embodiments: R² is halo, and R³ ishalo, —C₁₋₆alkyl optionally substituted with 1 to 5 fluoro atoms, or—O—C₀₋₃alkylene-phenyl; or R² is —C₁₋₆alkyl and R³ is halo or—C₁₋₆alkyl; or R² is —O—C₁₋₆alkyl and R³ is halo, —O—C₁₋₆alkyl, or—C₁₋₆alkyl optionally substituted with 1 to 5 fluoro atoms; or R² is—CN, —C(O)—C₁₋₆alkyl, or —C(O)O—C₁₋₄alkyl, and R³ is halo. In yet otherembodiments: R² is halo and R³ is halo or —O—C₀₋₃alkylene-phenyl; or R²is —C₁₋₆alkyl and R³ is halo or —C₁₋₆alkyl; or R² is —O—C₁₋₆alkyl and R³is halo; or R² is —C(O)—C₁₋₆alkyl and R³ is F; or R² is—C(O)O—C₁₋₄alkyl, and R³ is halo. In other embodiments: R² is Cl and R³is F, Cl or —O-phenyl; or R² is F and R³ is F, Cl or —O-phenyl; or R² is—CH₃, and R³ is F, Cl, or —CH₃; or R² is —OCH₃ and R³ is F; or R² is—C(O)CH₃ and R³ is F; or R² is —C(O)OCH₃ and R³ is F. In yet anotherembodiment, R² is —OCH₃ and R³ is F. In another embodiment, a is 1 to 5,and R¹ is as defined for formula I, which can be depicted as formulaVI′:

In another particular embodiment, R² and R³ are independently halo; a is1 and R¹ is halo, —C₁₋₆alkyl, or —O—C₁₋₆alkyl optionally substitutedwith 1 to 5 fluoro atoms; or a is 2, and each R¹ is independently haloor —SO₂—C₁₋₆alkyl. In other embodiments: R² and R³ are Cl, a is 1, andR¹ is 2-F, 3-F, 3-Cl, 2-CH₃, 3-CH₃, 3-OCH₃, or 3-OCF₃; or R² is Cl, R³is F, a is 2, one R¹ is 3-SO₂CH₃ and the other R¹ is 5-F. In anotherembodiment, R² and R³ are Cl, a is 1, and R¹ is 2-F, 3-Cl, or 3-OCH₃.

In another embodiment, R² and R⁴ are non-hydrogen moieties as definedfor formula I, and R³, R⁵ and R⁶ are H. In one particular embodiment, ais 0, which can be depicted as formula VII:

In one particular embodiment, R² is halo, —C₁₋₆alkyl optionallysubstituted with 1 to 5 fluoro atoms, —O—C₁₋₆alkyl, —C(O)—C₁₋₆alkyl, or—NO₂; and R⁴ is halo, —C₁₋₆alkyl, or —NO₂. In other embodiments: R² andR⁴ are independently halo; or R² is halo and R⁴ is halo, —C₁₋₆alkyl, or—NO₂; or R² is —C₁₋₆alkyl optionally substituted with 1 to 5 fluoroatoms and R⁴ is halo; or R² is —C₁₋₆alkyl and R⁴ is —NO₂; or R² is—O—C₁₋₆alkyl and R⁴ is halo or —NO₂; or R² is —C(O)—C₁₋₆alkyl and R⁴ ishalo; or R² is —C(O)O—C₁₋₄alkyl and R⁴ is halo; or R² is —NO₂ and R⁴ is—C₁₋₆alkyl. In yet other embodiments: R² is halo and R⁴ is halo or—C₁₋₆alkyl; or R² is —C₁₋₆alkyl or —O—C₁₋₆alkyl and R⁴ is halo; or R² is—C₁₋₆alkyl substituted with 1 to 5 fluoro atoms and R⁴ is Cl; or R² is—C(O)O—C₁₋₄alkyl and R⁴ is halo; or R² is —NO₂ and R⁴ is —C₁₋₆alkyl. Instill other embodiments: R² is Cl and R⁴ is Cl, F, or —CH₃; or R² is Fand R⁴ is F or Cl; or R² is —CH₃ and R⁴ is F or Cl; R² is —CH₂CH₃ and R⁴is F; or R² is —O—CH₃ and R⁴ is Cl or F; or R² is —CF₃ and R⁴ is Cl; orR² is —C(O)OCH₃ or —C(O)OCH₂CH₃, and R⁴ is Cl; or R² is —NO₂ and R⁴ is—CH₃. In additional embodiments: R² is Cl and R⁴ is F; or R² is —CH₂CH₃and R⁴ is F. In another embodiment, a is 1 to 5, and R¹ is as definedfor formula I, which can be depicted as formula VII′:

In one particular embodiment, a is 1 or 2; each R¹ is independentlyhalo, —C₁₋₆alkyl, —CN, or —SO₂—C₁₋₆alkyl; and R² and R⁴ areindependently halo, —C₁₋₆alkyl, —O—C₁₋₆alkyl, or —NO₂. In otherembodiments: R² and R⁴ are halo, a is 1, and R¹ is halo, —CN, or—SO₂—C₁₋₆alkyl; or R² and R⁴ are halo, a is 2, and each R¹ isindependently halo or —C₁₋₆alkyl; or R² is —O—C₁₋₆alkyl, R⁴ is halo, ais 1, and R¹ is halo; or R² is —CH₂CH₃ or —OCH₃, R⁴ is halo, a is 2, andeach R¹ is independently halo; or R² is —O—C₁₋₆alkyl, R⁴ is —NO₂, a is1, and R¹ is halo or —C₁₋₆alkyl. In other embodiments: R² and R⁴ are F,a is 1, and R¹ is 2-SO₂CH₃ or 4-SO₂CH₃; R² is F, R⁴ is Cl, a is 1, andR¹ is 2-Cl, 4-F, 4-Cl, 3-CN, or 4-CN; or R² is F, R⁴ is Cl, a is 2, oneR¹ is 3-F and the other R¹ is 5-F, 5-Cl, or 5-CH₃; or R² is F, R⁴ is Cl,a is 2, one R¹ is 3-CH₃ and the other R¹ is 5-CH₃; or R² is —OCH₃, R⁴ isF, a is 1, and R¹ is 2-Cl; or R² is —CH₂CH₃, R⁴ is F, a is 2, one R¹ is3-F and the other R¹ is 5-F; or R² is —OCH₃, R⁴ is F or Cl, a is 2, oneR¹ is 3-F and the other R¹ is 5-F; or R² is —OCH₃, R⁴ is —NO₂, a is 1,and R¹ is 3-Cl or 3-CH₃. In yet other embodiments: R² and R⁴ are halo, ais 1, and R¹ is —CN; or R² and R⁴ are halo, a is 2, and each R¹ isindependently halo or —C₁₋₆alkyl; or R² is —C₁₋₆alkyl or —O—C₁₋₆alkyl,R⁴ is halo, a is 2, each R¹ is independently halo. In other embodiments:R² is F, R⁴ is Cl, a is 1, and R¹ is 3-CN; or R² is F, R⁴ is Cl, a is 2,one R¹ is 3-F and the other R¹ is 5-F, 5-Cl, or 5-CH₃; or R² is —CH₂CH₃,R⁴ is F, a is 2, one R¹ is 3-F and the other R¹ is 5-F; or R² is —OCH₃,R⁴ is F or Cl, a is 2, one R¹ is 3-F and the other R¹ is 5-F.

In another embodiment, R² and R⁵ are non-hydrogen moieties as definedfor formula I, and R³, R⁴ and R⁶ are H. In one particular embodiment, ais 0, which can be depicted as formula VIII:

In one particular embodiment, R² is halo, —C₁₋₆alkyl, —O—C₁₋₆alkyl, —CN,—C(O)—C₁₋₆alkyl, or —C(O)O—C₁₋₄alkyl; and R⁵ is halo, —C₁₋₆alkyl, or—O—C₁₋₆alkyl. In other embodiments: R² is halo and R⁵ is halo or—C₁₋₆alkyl; or R² is —C₁₋₆alkyl and R⁵ is halo; or R² is —O—C₁₋₆alkyl or—CN, and R⁵ is halo; or R² is —O—C₁₋₆alkyl and R⁵ is —C₁₋₆alkyl; or R²is —C(O)—C₁₋₆alkyl and R⁵ is halo or —O—C₁₋₆alkyl; or R² is—C(O)O—C₁₋₄alkyl and R⁵ is halo. In yet other embodiments: R² is haloand R⁵ is halo or —C₁₋₆alkyl; or R² is —C₁₋₆alkyl or —O—C₁₋₆alkyl and R⁵is halo; or R² is —O—C₁₋₆alkyl and R⁵ is —C₁₋₆alkyl. In otherembodiments: R² is F and R⁵ is F; R² is Cl is F, Cl, Br, or —CH₃; or R²is Cl and R⁵ is F or Cl; or R² is —CH₃ and R⁵ is F or Cl; or R² is—O—CH₃ and R⁵ is F, Cl, or —CH₃. In additional embodiments: R² is F andR⁵ is F; R² is Cl and R⁵ is F or Cl; or R² is —O—CH₃ and R⁵ is F. Inanother embodiment, a is 1 to 5, and R¹ is as defined for formula I,which can be depicted as formula VIII′:

In one particular embodiment, a is 1 or 2; each R¹ is independently halo—C₁₋₆alkyl, or —O—C₁₋₆alkyl, where —O—C₁₋₆alkyl is optionallysubstituted with 1 to 5 fluoro atoms; R² is halo or —O—C₁₋₆alkyl; and R⁵is halo. In other embodiments: R² is F or Cl, R⁵ is Cl, a is 2 and eachR¹ is F; or R² is —O—CH₃, R⁵ is Cl; a is 1, and R¹ is Cl, 2-F, 3-F,3-CH₃, 3-OCH₃ or 3-OCF₃; or R² is —O—CH₃, R⁵ is F, a is 2, and each R¹is F. In yet another embodiment, R² is F or Cl, R⁵ is Cl, a is 2, andeach R¹ is F; or R² is —O—CH₃, R⁵ is Cl, a is 1, and R¹ is Cl; or R² is—O—CH₃, R⁵ is F, a is 2, and each R¹ is F. In another embodiment, R² isF or Cl, R⁵ is Cl, a is 2, one R¹ is 3-F and one R¹ is 5-F; or R² is—O—CH₃, R⁵ is Cl, a is 1 and R¹ is 3-Cl; or R² is —O—CH₃, R⁵ is F, a is2, one R¹ is 3-F and the other R¹ is 5-F.

In another embodiment, R² and R⁶ are non-hydrogen moieties as definedfor formula I, and R³, R⁴ and R⁵ are H. In one particular embodiment, ais 0, which can be depicted as formula IX:

In one particular embodiment, R² is halo, —C₁₋₆alkyl, —O—C₁₋₆alkyl, or—C(O)O—C₁₋₄alkyl; and R⁶ is halo or —C₁₋₆alkyl. In other embodiments: R²is F and R⁶ is F, Cl, or —CH₃; R² is Cl and R⁶ is F or Cl; or R² is —CH₃and R⁶ is Cl or —CH₂CH₃; or R² is —OCH₃ and R⁶ is F; or R² is —C(O)OCH₃and R⁶ is Cl. In yet other embodiments: R² is halo, —C₁₋₆alkyl, or—O—C₁₋₆alkyl, and R⁶ is halo; or R² is halo and R⁶ is —C₁₋₆alkyl; or R²is —C(O)O—C₁₋₄alkyl and R⁶ is halo. In other embodiments: R² is F or Cland R⁶ is F or Cl; or R² is F and R⁶ is —CH₃; or R² is —CH₃ and R⁶ isCl; or R² is —OCH₃ and R⁶ is F; or R² is —C(O)OCH₃ and R⁶ is Cl. Inadditional embodiments: R² is F or Cl and R⁶ is F or Cl. In anotherembodiment, a is 1 to 5, and each R¹ is as defined for formula I, whichcan be depicted as formula IX′:

In one particular embodiment, a is 1 or 2; each R¹ is independentlyhalo, —C₁₋₆alkyl, —O—C₁₋₆alkyl optionally substituted with 1 to 5 fluoroatoms, —CN, —SO₂—C₁₋₆alkyl, or —C(O)NH₂; R² is halo; and R⁶ is halo or—O—C₁₋₆alkyl. In other embodiments: R² and R⁶ are halo, a is 1, and R¹is halo, —C₁₋₆alkyl, —O—C₁₋₆alkyl optionally substituted with 1 to 5fluoro atoms, —CN, —SO₂—C₁₋₆alkyl, or —C(O)NH₂; or R² and R⁶ are halo, ais 2, one R¹ is halo, and the other R¹ is halo or —C₁₋₆alkyl; or R² ishalo and R⁶ is —O—C₁₋₆alkyl, a is 1 or 2, and each R¹ is independentlyhalo. In yet other embodiments: R² and R⁶ are Cl, a is 1 and R¹ is halo,—C₁₋₆alkyl, —O—C₁₋₆alkyl, —CN, or —C(O)NR^(a)R^(b), where R^(a) andR^(b) are H; or R² and R⁶ are Cl, a is 2, one R¹ is halo and the otherR¹ is halo or —C₁₋₆alkyl; or R² is F, R⁶ is Cl, a is 2, and R¹ isindependently halo; or R² is F and R⁶ is —OCH₃, a is 1 or 2, and each R¹is independently halo. In other embodiments: R² and R⁶ are Cl, a is 1and R¹ is 2-Cl, 3-Cl, 4-Cl, 4-F, 3-CH₃, 3-OCH₃, 3-CN, 4-CN, 3-C(O)NH₂,or 4-C(O)NH₂; or R² and R⁶ are Cl, a is 2, one R¹ is 3-F, and the otherR¹ is 5-F, 5-Cl, or 5-CH₃; or R² is F, R⁶ is Cl, a is 2, one R¹ is 3-Fand the other R¹ is 5-F; or R² is F, R⁶ is —OCH₃, a is 1, and R¹ is2-Cl; or R² is F, R⁶ is —OCH₃, a is 1, and R¹ is 2-Cl; or R² is F, R⁶ is—OCH₃, a is 2, one R¹ is 3-F and the other R¹ is 5-F.

In another embodiment, R³ and R⁴ are non-hydrogen moieties as definedfor formula I, and R², R⁵ and R⁶ are H. In one particular embodiment, ais 0, which can be depicted as formula X:

In one particular embodiment, R³ is halo, —C₁₋₆alkyl optionallysubstituted with 1 to 5 fluoro atoms, or —O—C₁₋₆alkyl; and R⁴ is halo,—C₁₋₆alkyl, or —O—C₁₋₆alkyl. In other embodiments: R³ is halo and R⁴ ishalo or —C₁₋₆alkyl; or R³ is —C₁₋₆alkyl optionally substituted with 1 to5 fluoro atoms and R⁴ is halo; or R is —O—C₁₋₆alkyl and R⁴ is halo or—O—C₁₋₆alkyl. In yet other embodiments, R³ is halo and R⁴ is —C₁₋₆alkyl.In other embodiments: R³ is F and R⁴ is —CH₃. In another embodiment, ais 1 to 5, and each R¹ is as defined for formula I, which can bedepicted as formula X′:

In another embodiment, R³ and R⁵ are non-hydrogen moieties as definedfor formula I, and R², R⁴ and R⁶ are H. In one embodiment, a is 0, whichcan be depicted as formula XI:

In one particular embodiment, R³ and R⁵ are independently halo or—C₁₋₆alkyl. In other embodiments: R³ is F and R⁵ is F, Cl or —CH₃; or R³is Cl and R⁵ is Cl or Br; or R³ and R⁵ are —CH₃. In yet anotherembodiment, R³ and R⁵ are independently halo. In other embodiments: R³and R⁵ are independently F or Cl. In another embodiment, R³ and R⁵ areF. In another embodiment, a is 1 to 5 and each R¹ is as defined forformula I, which can be depicted as formula XI′:

In one particular embodiment, R³ and R⁵ are independently halo; a is 1or 2; each R¹ is independently halo, —C₁₋₆alkyl, or —O—C₁₋₆alkyl. Inother embodiments: R³ and R⁵ are Cl, a is 1 and R¹ is 2-Cl, 3-Cl, 4-Cl,2-F, 3-F, 4-F, 2-CH₃, 3-CH₃, 4-CH₃, or 3-OCH₃, or a is 2, one R¹ is 3-Fand the other R¹ is 5-F, 5-Cl or 5-CH₃; or R³ and R⁵ are F, a is 1, andR¹ is 2-Cl. In another embodiment, R³ and R⁵ are Cl, a is 1, and R¹ is2-Cl, 4-F, or 4-CH₃; or a is 2; one R¹ is 3-F and the other R¹ is 5-F,5-Cl or 5-CH₃.

In another embodiment, R², R³, and R⁴ are non-hydrogen moieties asdefined for formula I, and R⁵ and R⁶ are H. In one particularembodiment, a is 0, which can be depicted as formula XII:

In one particular embodiment, R² is halo or —C(O)—C₁₋₆alkyl; R³ is halo,—C₁₋₆alkyl, or —O—C₁₋₆alkyl; and R⁴ is halo or —C₁₋₆alkyl. In otherembodiments: R², R³ and R⁴ are independently halo; or R² and R³ areindependently halo, and R⁴ is —C₁₋₆alkyl; or R² and R⁴ are independentlyhalo, and R³ is —C₁₋₆alkyl. In another embodiment, R², R³ and R⁴ are F;or R² is F, R³ is F, and R⁴ is Cl or —CH₃; or R² is F, R³ is —CH₃, andR⁴ is F; or R² and R⁴ are Cl and R³ is F. In another embodiment, a is 1to 5 and each R¹ is as defined for formula I, which can be depicted asformula XII′:

In one particular embodiment, a is 1 or 2; and R¹, R², R³, and R⁴ areindependently halo. In other embodiments: R², R³, and R⁴ are F, a is 1and R¹ is 2-halo, or a is 2, one R¹ is 3-halo and the other R¹ is5-halo. In yet another embodiment, R², R³, and R⁴ are F, a is 2, one R¹is 3-halo and the other R¹ is 5-halo. In another embodiment, R², R³, andR⁴ are F, a is 2, one R¹ is 3-F and the other R¹ is 5-F.

In another embodiment, R², R³, and R⁵ are non-hydrogen moieties asdefined for formula I, and R⁴ and R⁶ are H. In one particularembodiment, a is 0, which can be depicted as formula XIII:

In one particular embodiment, R² is halo, —O—C₁₋₆alkyl, or—C(O)—C₁₋₆alkyl; R³ is halo; and R⁵ is halo or —C₁₋₆alkyl optionallysubstituted with 1 to 5 fluoro atoms. In other embodiments: R², R³, andR⁵ are independently halo; or R² is —O—C₁₋₆alkyl or —C(O)—C₁₋₆alkyl, andR³ and R⁴ are independently halo; or R² and R³ are independently halo,and R⁵ is —C₁₋₆alkyl optionally substituted with 1 to 5 fluoro atoms. Inother embodiments: R², R³, and R⁵ are F; or R², R³, and R⁵ are Cl; or R²is Cl, R³ is F, and R⁴ is Cl; or R² is —O—CH₃, R³ is F, and R⁴ is F. Inanother embodiment, a is 1 to 5 and each R¹ is as defined for formula I,which can be depicted as formula XIII′:

In one particular embodiment, a is 1 or 2; and each R¹, R², R³, and R⁵are independently halo. In other embodiments: R², R³, and R⁵ are F, a is1, and R¹ is 2-Cl; or R², R³, and R⁵ are F, a is 2, one R¹ is 3-F andthe other R¹ is 5-F; or R², R³, and R⁵ are Cl, a is 1, and R¹ is 2-Cl or4-Cl; or R², R³, and R⁵ are Cl, a is 2, one R¹ is 3-F and the other R¹is 5-F. In yet other embodiments: R², R³, and R⁵ are F, a is 1, and R¹is 2-Cl; or R², R³, and R⁵ are F, a is 2, one R¹ is 3-F and the other R¹is 5-F; or R², R³, and R⁵ are Cl, a is 1, and R¹ is 2-Cl; or R², R³, andR⁵ are Cl, a is 2, one R¹ is 3-F and the other R¹ is 5-F.

In another embodiment, R², R³, and R⁶ are non-hydrogen moieties asdefined for formula I, and R⁴ and R⁵ are H. In one particularembodiment, a is 0, which can be depicted as formula XIV:

In one particular embodiment, R² is halo, —C(O)—C₁₋₆alkyl, or—C(O)O—C₁₋₄alkyl; R³ is halo, —C₁₋₆alkyl, or —O—C₁₋₆alkyl; and R⁶ ishalo, —C₁₋₆alkyl, or —O—C₁₋₆alkyl. In yet another embodiment, R² ishalo, R³ is halo, and R⁶ is halo or —O—C₁₋₆alkyl; or R² is halo, R³ is—C₁₋₆alkyl or —O—-C₁₋₆alkyl, and R⁶ is halo; or R² is —C(O)—C₁₋₆alkyl,R³ is halo, and R⁶ —C₁₋₆alkyl; or R² is —C(O)O—C₁₋₄alkyl and R³ and R⁶are halo. In still another embodiment, R² is halo, is halo and R⁶ ishalo or —O—C₁₋₆alkyl; or R² is halo, R³ is —C₁₋₆alkyl or —O—C₁₋₆alkyl,and R⁶ is halo. In other embodiments: R² is F, R³ is F, and R⁶ is F or—OCH₃; or R² is F, R³ is Cl or —OCH₃, and R⁶ is F; or R² is F, R³ is—CH₃, and R⁶ is F or Cl; or R² is Cl, R³ is Cl, and R⁶ is Cl or F; or R²is Cl, R³ is F, and R⁶ is F or —OCH₃; or R² is Cl, R⁶ is F and —CH₃, andR⁶ is F or Cl; or R² is F, R⁶ is Cl and R³ is Cl or —OCH₃; or R² is Cl,R⁶ is F and R³ is —OCH₃. In another embodiment, a is 1 to 5 and each R¹is as defined for formula I, which can be depicted as formula XIV′:

In one particular embodiment, a is 1 or 2; each R¹ is independentlyhalo, —C₁₋₆alkyl, —C₀₋₆alkylene-OH, —CN, —SO₂—C₁₋₆alkyl, or —C(O)NH₂; R²is halo; R³ is halo or —C₁₋₆alkyl; and R⁶ is halo or —O—C₁₋₆alkyl. Inother embodiments: R² is halo, R³ is halo, R⁶ is halo, a is 1, and R¹ ishalo, —CN, or —C(O)NR^(a)R^(b), where R^(a) and R^(b) are H; R² is halo,R³ is —C₁₋₆alkyl, R⁶ is halo, a is 1, and R¹ is halo, —C₀₋₆alkylene-OH,—CN, or —SO₂—C₁₋₆alkyl; or R² is halo, R³ is halo, R⁶ is halo or—O—C₁₋₆alky, a is 2, and each R¹ is independently halo; or R² is halo,R³ is —C₁₋₆alkyl, R⁶ is halo, a is 2, one R¹ is halo and the other R¹ ishalo or —C₁₋₆alkyl. In yet other embodiments: R² is halo, R³ is halo, R⁶is halo, a is 1, and R¹ is halo, —CN, or —C(O)NR^(a)R^(b), where R^(a)and R^(b) are H; R² is halo, R³ is —C₁₋₆alkyl, R⁶ is halo, a is 1, andR¹ is halo, —C₀₋₆alkylene-OH, or —CN; or R² is halo, R³ is halo, R⁶ ishalo or —O—C₁₋₆alky, a is 2, and each R¹ is independently halo; or R² ishalo, R³ is —C₁₋₆alkyl, R⁶ is halo, a is 2, one R¹ is halo and the otherR¹ is halo or —C₁₋₆alkyl. In other embodiments: R² is Cl, R³ is Cl, R⁶is Cl, a is 1, and R¹ is 2-Cl; or R² is Cl, R³ is —CH₃, R⁶ is Cl, a is1, and R¹ is 4-Cl, 3-CN, 4-CN, or 3-CH₂OH; or R² is Cl, R³ is Cl, R⁶ isF, a is 1, and R¹ is 3-CN or 3-C(O)NH₂; or R² is F, R³ is F or Cl, R⁶ isF, a is 2, one R¹ is 3-F and the other R¹ is 5-F; or R² is Cl, R³ is Cl,R⁶ is Cl, a is 2, one R¹ is 3-F and the other R¹ is 5-F; or R² is Cl, R³is F, R⁶ is F, a is 2, one R¹ is 3-F and the other R¹ is 5-F; or R² isF, R³ is F, R⁶ is F or —OCH₃, a is 2, one R¹ is 3-F and the other R¹ is5-F; or R² is F, R³ is —CH₃, R⁶ is F or Cl, one R¹ is 3-F and the otherR¹ is 5-F; or R² is Cl, R³ is —CH₃, R⁶ is Cl, a is 2, one R¹ is 3-F andthe other R¹ is 5-Cl, 5-F, or 5-CH₃; or R² is Cl, R³ is —CH₃, R⁶ is F, ais 2, one R¹ is 3-F and the other R¹ is 5-F.

In another embodiment, R², R⁴, and R⁵ are non-hydrogen moieties asdefined for formula I, and R³ and R⁶ are H. In one particularembodiment, a is 0, which can be depicted as formula XV:

In one particular embodiment, R² is halo, —O—C₁₋₆alkyl, or—C(O)—C₁₋₆alkyl; R⁴ is halo or —C₁₋₆alkyl; and R⁵ is halo or —C₁₋₆alkyl.In yet another embodiment, R² is halo or —O—C₁₋₆alkyl; and R⁴ and R⁵ areindependently halo; or R² is halo and R⁴ and R⁵ are independently—C₁₋₆alkyl; or R² is —C(O)—C₁₋₆alkyl, R⁴ is —C₁₋₆alkyl, and R⁵ is halo;or R² and R⁵ are independently halo, and R⁴ is —C₁₋₆alkyl. In otherembodiments: R², R⁴, and R⁵ are F; or R² is —OCH₃, R⁴ is Cl, and R⁵ isF; or R² is Cl, R⁴ is —CH₃, and R⁵ is F. In another embodiment, a is 1to 5 and each R¹ is as defined for formula I, which can be depicted asformula XV′:

In one particular embodiment, a is 2; each R¹ is independently halo; andR², R⁴, and R⁵ are independently halo or —O—C₁₋₆alkyl. In yet anotherembodiment, a is 2; each R¹ is independently halo; R² is halo or—O—C₁₋₆alkyl; and R⁴ and R⁵ are independently halo. In anotherembodiment, one R¹ is 3-F and the other R¹ is 5-F; R², R⁴, and R⁵ are F;or R² is —OCH₃, R⁴ is Cl, and R⁵ is F.

In another embodiment, R², R⁴, and R⁶ are non-hydrogen moieties asdefined for formula I, and R³ and R⁵ are H. In one particularembodiment, a is 0, which can be depicted as formula XVI:

In one particular embodiment, R², R⁴, and R⁶ are independently halo,—C₁₋₆alkyl, —O—C₁₋₆alkyl, —C(O)—C₁₋₆alkyl, or —C(O)O—C₁₋₄alkyl. In otherembodiments: R² is F, —CH₂CH₃, or —C(O)CH₃, R⁴ is F, and R⁶ is F; or R²is F, R⁴ is —OCH₃, and R⁶ is F; or R² is F, R⁴ is Cl, and R⁶ is F, Cl,or Br; or R² is Cl, R⁴ is F or Cl, and R⁶ is Cl; or R² is Cl, R⁴ is Cl,and R⁶ is —CH₃; or R² is Cl, R⁴ is —CH₃, and R⁶ is Cl; or R² is Br, R⁴is F, and R⁶ is Br; or R² is —CH₃, R⁴ is Cl, and R⁶ is Cl; or R² is—CH₃, R⁴ is —CH₃, and R⁶ is —CH₃; or R² is —C(O)OCH₃ and R⁴ and R⁶ areF. In yet other embodiments: R² is F, —CH₂CH₃, or —C(O)CH₃, R⁴ is F, andR⁶ is F; or R² is F, R⁴ is Cl, and R⁶ is F or Cl; or R² is Cl, R⁴ is F,and R⁶ is Cl; or R² is —C(O)OCH₃ and R⁴ and R⁶ are F. In anotherembodiment, R² is F, R⁴ is F, and R⁶ is F. In another embodiment, a is 1to 5 and each R¹ is as defined for formula I, which can be depicted asformula XVI′:

In one particular embodiment, a is 1 or 2; each R¹ is independentlyhalo, —CN, —SO₂—C₁₋₆alkyl, or —C(O)NR^(a)R^(b), where R^(a) and R^(b)are H; and R², R⁴, and R⁶ are independently halo or —C₁₋₆alkyl. In otherembodiments: R² is F, R⁴ is Cl, R⁶ is F, a is 1, and R¹ is 2-Cl; or R²is Cl, R⁴ is F, R⁶ is Cl, a is 1, and R¹ is 2-Cl; or R² is F, R⁴ is F,R⁶ is F, as is 1 R¹ is 3-CN, 4-CN, 3-C(O)NH₂, 4-C(O)NH₂, or 4-SO₂CH₃; orR² is F, R⁴ is F, R⁶ is F, a is 2, one R¹ is 3-F and the other R¹ is5-F; or R² is Cl, R⁴ is —CH₃; R⁶ is Cl, a is 2, and one R¹ is 3-F andthe other R¹ is 5-F. In yet other embodiments: R² is F, R⁴ is F, R⁶ isF, a is 1 and R¹ is 3-CN or 3-C(O)NH₂; or R is F, R⁴ is F, R⁶ is F, a is2, one R¹ is 3-F and the other R¹ is 5-F.

In another embodiment, R³, R⁴, and R⁵ are non-hydrogen moieties asdefined for formula I, and R² and R⁶ are H. In one particularembodiment, a is 0, which can be depicted as formula XVII:

In another embodiment, R³ is halo or —C₁₋₆alkyl; R⁵ is halo or—C₁₋₆alkyl; and R⁴ is halo or —O—C₁₋₆alkyl. In other embodiments: R³ andR⁵ are halo, and R⁴ is halo or —O—C₁₋₆alkyl; or R³ and R⁵ are C₁₋₆alkyl,and R⁴ is halo. In another embodiment, a is 1 to 5 and each R¹ is asdefined for formula I, which can be depicted as formula XVII′:

In another embodiment, R², R³, R⁴, and R⁵ are non-hydrogen moieties asdefined for formula I, and R⁶ is H. In one particular embodiment, a is0, which can be depicted as formula XVIII:

In another embodiment, a is 1 to 5 and each R¹ is as defined for formulaI, which can be depicted as formula XVIII′:

In another embodiment, R², R³, R⁴, and R⁶ are non-hydrogen moieties asdefined for formula I, and R⁵ is H. In one particular embodiment, a is0, which can be depicted as formula XIX:

In another embodiment, a is 1 to 5 and each R¹ is as defined for formulaI, which can be depicted as formula XIX′:

In another embodiment, R², R³, R⁵, and R⁶ are non-hydrogen moieties asdefined for formula I, and R⁴ is H. In one particular embodiment, a is0, which can be depicted as formula XX:

In one particular embodiment, R², R³, R⁵, and R⁶ are independently haloor —C₁₋₆alkyl. In other embodiments: R², R³, R⁵, and R⁶ are F; or R²,R³, R⁵, and R⁶ are Cl; or R² and R⁶ are Cl, and R³ and R⁵ are F; or R²,R³, R⁵, and R⁶ are —CH₃; or R², R³, and R⁵ are F, and R⁶ is Cl. In yetanother embodiment, R², R³, R⁵, and R⁶ are independently halo. Inanother embodiment, R², R³, R⁵, and R⁶ are F; or R², R³, R⁵, and R⁶ areCl; or R² and R⁶ are Cl, and R³ and R⁵ are F; or R², R³, and R⁵ are F,and R⁶ is Cl. In another embodiment, a is 1 to 5 and each R¹ is asdefined for formula I, which can be depicted as formula XX′:

In one particular embodiment, R¹ is halo, —C₀₋₂alkylene-COOH, —CHO,—C(O)O—C₁₋₄alkyl, —C₀₋₁alkylene-NR^(a)R^(b), or —C(O)NR^(a)R^(b); andR², R³, R⁵, and R⁶ are independently halo. In other embodiments: R² andR⁶ are Cl, R³ and R⁵ are F; a is 1 and R¹ is 2-Cl, 3-COOH, 3-CHO,3-C(O)OCH₃, 3-C(O)OCH₂CH₃, 3-CH₂NH(CH₂CH₃), 3-CH₂N(CH₃)(CH₂CH₃),3-C(O)—NHCH₂CH₃, or 3-C(O)—N(CH₃)CH₂CH; or a is 2, one R¹ is 3-F and theother R¹ is F. In yet another embodiment, R¹, R², R³, R⁵, and R⁶ areindependently halo. In other embodiments: R² and R⁶ are Cl, R³ and R⁵are F; a is 1 and R¹ is 2-Cl or a is 2, one R¹ is 3-F and the other R¹is F.

In another embodiment, R², R³, R⁴, R⁵, and R⁶ are non-hydrogen moietiesas defined for formula I. In one particular embodiment, a is 0, whichcan be depicted as formula XXI:

In one particular embodiment, R² is halo, —C(O)—C₁₋₆alkyl, or—C(O)O—C₁₋₄alkyl; R³, R⁵, and R⁶ are independently halo; and R⁴ is haloor —C₁₋₆alkyl optionally substituted with 1 to 5 fluoro atoms. In yetother embodiments: R², R³, R⁴, R⁵, and R⁶ are F; or R², R³, R⁵, and R⁶are F, and R⁴ is F, Cl, or —CF₃; or R², R⁴, and R⁶ are Cl and R³ and R⁵are F; or R² is —C(O)—C₁₋₆alkyl or —C(O)O—C₁₋₄alkyl, and R³, R⁴, R⁵, andR⁶ are F. In still another embodiment, R², R³, R⁴, R⁵, and R⁶ are F; orR is —C(O)O—C₁₋₄alkyl, and R³, R⁴, R⁵, and R⁶ are F. In yet anotherembodiment, R², R³, R⁴, R⁵, and R⁶ are F. In another embodiment, a is 1to 5 and each R¹ is as defined for formula I, which can be depicted asformula XXI′:

In one embodiment, the compounds of the invention exhibit a NET pK_(i)≧8and a SERT K_(i)/NET K_(i) in the range of 0.1-100. In reporting suchratios herein, all ratios have been rounded off to the nearest tenth. Inone particular embodiment, such compounds have formula (II)-(XXI) or(II′)-(XXI′).

In addition, particular compounds of formula I that are of interestinclude those set forth in the Examples below, as well apharmaceutically acceptable salt thereof.

General Synthetic Procedures

Compounds of the invention can be prepared from readily availablestarting materials using the following general methods, the proceduresset forth in the Examples, or by using other methods, reagents, andstarting materials that are known to those skilled in the art. Althoughthe following procedures may illustrate a particular embodiment of theinvention, it is understood that other embodiments of the invention canbe similarly prepared using the same or similar methods or by usingother methods, reagents and starting materials known to those ofordinary skill in the art. It will also be appreciated that wheretypical or preferred process conditions (i.e., reaction temperatures,times, mole ratios of reactants, solvents, pressures, etc.) are given,other process conditions can also be used unless otherwise stated. Whileoptimum reaction conditions will typically vary depending on variousreaction parameters such as the particular reactants, solvents andquantities used, those of ordinary skill in the art can readilydetermine suitable reaction conditions using routine optimizationprocedures.

Additionally, as will be apparent to those skilled in the art,conventional protecting groups may be necessary or desired to preventcertain functional groups from undergoing undesired reactions. Thechoice of a suitable protecting group for a particular functional groupas well as suitable conditions and reagents for protection anddeprotection of such functional groups are well-known in the art.Protecting groups other than those illustrated in the proceduresdescribed herein may be used, if desired. For example, numerousprotecting groups, and their introduction and removal, are described inGreene and Wuts, Protecting Groups in Organic Synthesis, Third Edition,Wiley, New York, 1999, and references cited therein.

More particularly, in the schemes below, P represents an“amino-protecting group,” a term used herein to mean a protecting groupsuitable for preventing undesired reactions at an amino group.Representative amino-protecting groups include, but are not limited to,t-butoxycarbonyl (BOC), trityl (Tr), benzyloxycarbonyl (Cbz),9-fluorenylmethoxycarbonyl (Fmoc), formyl, benzyl, and the like.Standard deprotection techniques and reagents such as TFA in DCM or HClin 1,4-dioxane, methanol, or ethanol, are used to remove protectinggroups, when present. For example, a BOC group can be removed using anacidic reagent such as hydrochloric acid, trifluoroacetic acid and thelike; while a Cbz group can be removed by employing catalytichydrogenation conditions such as H₂ (1 atm), 10% Pd/C in an alcoholicsolvent.

Suitable inert diluents or solvents for use in these schemes include, byway of illustration and not limitation, tetrahydrofuran (THF),acetonitrile, N,N-dimethylformamide (DMF), dimethylsulfoxide (DMSO),toluene, dichloromethane (DCM), chloroform (CHCl₃), and the like.

All reactions are typically conducted at a temperature within the rangeof about −78° C. to 110° C., for example at room temperature. Reactionsmay be monitored by use of thin layer chromatography (TLC), highperformance liquid chromatography (HPLC), and/or LCMS until completion.Reactions may be complete in minutes, may take hours, typically from 1-2hours and up to 48 hours, or days, such as up to 3-4 days. Uponcompletion, the resulting mixture or reaction product may be furthertreated in order to obtain the desired product. For example, theresulting mixture or reaction product may be subjected to one or more ofthe following procedures: dilution (for example with saturated NaHCO₃);extraction (for example, with ethyl acetate, CHCl₃, DCM, aqueous HCl);washing (for example, with DCM, saturated aqueous NaCl, or saturatedaqueous NaHCO₃); drying (for example, over MgSO₄ or Na₂SO₄, or invacuo); filtration; being concentrated (for example, in vacuo); beingredissolved (for example in a 1:1 acetic acid:H₂O solution); and/orpurification (for example by preparative HPLC or reverse phasepreparative HPLC).

By way of illustration, compounds of formula I, as well as their salts,can be prepared by one or more of the following schemes.

While Scheme I illustrates formation of the (S,R) enantiomer of thecompound of formula I, the (R,S) enantiomer of the compound of formula Ican be made in a similar manner, using the (R) stereoisomer compound 1′as the starting material, which forms the (R,S) and (R,R) alcoholcompounds 5′ and 6′, respectively:

Preparation of Compound 2 or 2′

Compound 2 can be prepared by the 2,2,6,6-tetramethyl-1-piperidinyloxy,free radical (TEMPO) mediated oxidation of compound 1. Compound 1, whereP is Boc or benzyl, is commercially available. Alternately, Compound 2can be prepared by oxidizing compound 1 using any oxidizing agentsuitable for converting a primary alcohol into an aldehyde.Representative oxidizing agents include, for example, dimethylsulfoxide, Collin's reagent, Corey's reagent, pyridinium dichromate andthe like.

Compound 2′ can be prepared in a similar manner, usingR-Boc-3-pyrrolidinemethanol, also known as(R)-3-hydroxymethylpyrrolidine-1-carboxylic acid t-butyl ester, asstarting material compound 1′. Thus, one embodiment of the inventionrelates to the preparation of compound 2 or compound 2′, by reactingcompound 1 or compound 1′, respectively, with sodium hypochlorite in thepresence of TEMPO and potassium bromide in water. This method isparticularly useful by minimizing the amount of racemization that canoccur when the alcohol 1 or 1′ is oxidized.

Preparation of Compound 4

Compound 4 is a Grignard reagent, and serves to introduce theunsubstituted (a=0) or substituted phenyl group into compound 2.Compound 4 can be readily prepared by treating a compound 3 (forexample, where X is bromo or iodo) with magnesium metal. See forexample, Knochel et al. (2003) Angew. Chem., Int. Ed. 42(36):4302-4320.Compound 4 may also be commercially available, examples of which includephenylmagnesium bromide.

Alternately, other reagents can be used to introduce the phenyl groupinto compound 2 or 2′. For example, compound 4 can be replaced with:

in Scheme I. Both compounds are commercially available or can beprepared by techniques that are known in the art.

Preparation and Separation of Compounds 5 and 6

The Grignard reaction between compound 2 and compound 4 is typicallyconducted using standard Grignard reaction conditions. For example,compound 2, in a suitable solvent such as THF, is cooled under nitrogento about −78° C. Compound 4 in a suitable solvent such as THF is addeddropwise and the solution is allowed to warm to room temperature,typically overnight. The reaction is then quenched, for example usingsaturated NH₄Cl. Purification and separation by preparative HPLC orcrystallization will then yield compounds 5 and 6. Examples of compounds5 and 6 include (S)-3-((R)-hydroxyphenylmethyl)pyrrolidine-1-carboxylicacid t-butyl ester and(S)-3-((S)-hydroxyphenylmethyl)pyrrolidine-1-carboxylic acid t-butylester, respectively.

Compounds 5 and/or 6 can also be prepared by reduction of thecorresponding ketone (compound 11) as shown in Scheme II.

Similarly, compound 2′ as the starting material will yield compounds 5′and 6′. Examples compounds 5′ and 6′ include(R)-3-((S)-hydroxyphenylmethyl)pyrrolidine-1-carboxylic acid t-butylester and (R)-3-((R)-hydroxyphenylmethyl)pyrrolidine-1-carboxylic acidt-butyl ester, respectively.

Ullmann Preparation of Compounds of Formula I

Compound 5 can then be coupled to an appropriate aryl iodide (compound7′) under Ullmann reaction conditions to provide compound 8. The Ullmannreaction is typically conducted in the presence of a copper(I)iodide/1,10-phenanthroline catalyst and a base such as cesium carbonate,in an appropriate solvent such as toluene or DMF. The reaction vessel issealed and the mixture is heated at about 100-110° C. until the reactionis complete, typically about 3 days, yielding compound 8, which is thendeprotected to yield the compound of formula (I). This final step isconducted under standard deprotection conditions, which will varydepending upon the protecting group used. For example, removal of theBOC group can be done using HCl and ethanol.

In a similar manner, the (R,S) compound 8′ can be formed by usingcompound 5′:

Examples of compound 5 include(S)-3-((R)-hydroxyphenylmethyl)pyrrolidine-1-carboxylic acid t-butylester. Examples of compound 5′ include(R)-3-(S)-hydroxyphenylmethyl)pyrrolidine-1-carboxylic acid t-butylester. Examples of compound 7′ include 2,4-difluoro-1-iodobenzene,4-chloro-2-fluoro-1-iodobenzene, and 1,3-dichloro-5-iodobenzene.

S_(N)Ar Preparation of Compounds of Formula I

Alternatively, compound 8 can be prepared by reacting compound 5 with anappropriate aryl fluoride (compound 7″) using a nucleophilic aromaticsubstitution reaction (S_(N)Ar). For example, sodium hydride is slowlyadded to compound 5 that has been dissolved in an appropriate solventsuch as DMF. An appropriate aryl fluoride (compound 7″) is then addedand the mixture is stirred at about 70° C. until the reaction iscomplete, about 3 hours, yielding compound 8, which is then deprotectedto yield the compound of formula (I). Examples of compound 5 include(S)-3-((R)-hydroxyphenylmethyl)pyrrolidine-1-carboxylic acid t-butylester. Examples of compound 7″ include1-fluoro-2-methanesulfonyl-benzene, 1-fluoro-3-nitrobenzene,1-(2-fluorophenyl)ethanone, 2-chloro-1,3-difluorobenzene, and2-fluorobenzoic acid methyl ester.

In a similar manner, the (R,S) compound 8′ can be formed by usingcompound 5′:

Mitsunobu Preparation of Compounds of Formula I

Compound 6 can also be converted into compound 8 using the Mitsunobucoupling reaction (Mitsunobu and Yamada (1967) M. Bull. Chem. Soc. JPN.40:2380-2382). This reaction is typically conducted using standardMitsunobu coupling conditions, using a redox system containing anazodicarboxylate such as diethyl azodicarboxylate or diisopropylazodicarboxylate (DIAD) and a phosphine catalyst such astriphenylphosphine (PPh₃). For example, compound 6 is combined with anappropriate phenol (compound 7′″), and PPh₃ in an appropriate solventsuch as THF. While the mixture is sonicated, DIAD is added, yieldingcompound 8, which is then deprotected to yield the compound of formula(I). Typically, approximately equimolar amounts of PPh₃ and DIAD areused. Examples of compound 6 include(S)-3-((S)-hydroxyphenylmethyl)pyrrolidine-1-carboxylic acid t-butylester. Examples of compound 7′″ include2-chloro-6-fluoro-3-methylphenol, 2-chloro-3,5-difluorophenol,2-chloro-3,6-difluorophenol, 2,6-dichloro-3,5-difluorophenol, and2,4,6-trifluorophenol, of which are commercially available.

In a similar manner, the (R,S) compound 8′ can be formed by using thecompound 6′.

Examples of compound 6′ include(R)-3-((R)-hydroxyphenylmethyl)pyrrolidine-1-carboxylic acid t-butylester.

As shown in Scheme II, compound 9 is first converted to thecorresponding Weinreb amide which is then reacted with a Grignardreagent to form compound 11. The first reaction can be conducted usingeither racemic or chiral starting material 9. Since the subsequentreactions do not typically affect the stereochemistry of this startingchiral center, the stereochemistry desired at this chiral center forlater intermediates and products can selected by proper choice ofstarting material 9.

Preparation of Compound 11

The Weinreb amide 10 is typically synthesized using standard reactionconditions from the corresponding carboxylic acid, compound 9. Forexample, compound 9 (mixture of (R) and (S) enantiomers), appropriatecoupling reagents (for example HOBt and HCTU), andN,O-dimethylhydroxylamine HCl are combined with an appropriate solventsuch as DMF. The mixture is cooled, typically at 0° C. using an icebath, followed by the slow addition of a base such as DIPEA. The mixtureis allowed to warm to room temperature and stirred until the reaction iscomplete (typically about 15 hours) to yield a mixture of the (R) and(S) enantiomers of compound 10.

Compound 10 is then reacted with a Grignard reagent 4 to providecompound 11. For example, compound 10, in a suitable solvent such asTHF, is cooled under nitrogen to about −100° C. Compound 4 in a suitablesolvent such as THF is added dropwise and the solution is allowed towarm to room temperature, typically for about 30 minutes to 2 hours.After cooling in an ice bath, the reaction is quenched, for example bythe slow addition of water. Purification by flash chromatography willthen yield compound 11, which is a mixture of the (R) and (S)enantiomers. Examples of starting material compound 9 includepyrrolidine-1,3-dicarboxylic acid 1-t-butyl ester.

The (S) compound 11′ can be prepared in a similar manner as the mixture,but using (3S)-Boc-β-Proline-OH, also known as(S)-pyrrolidine-1,3-dicarboxylic acid 1-t-butyl ester, as the compound9′ starting material:

The (R) compound 11″ can be prepared in a similar manner, but using(R)-1-N-Boc-β-Proline, also known as (R)-pyrrolidine-1,3-dicarboxylicacid 1-t-butyl ester, as the compound 9″ starting material:

Preparation of Compound 5 and Compound 6

A mixture of compound 5 (S,R) and compound 6 (S,S) can be prepared from(S) compound 11′. Compound 11′ in an appropriate solvent such asmethanol (typically at 0° C.) is combined with a reducing agent such assodium borohydride. The mixture is allowed to warm to room temperatureand stirred until the reaction is complete (typically about 1 hour). Theresulting mixture of compounds 5 (S,R) and 6 (S,S) may be purified byflash chromatography. In a similar manner, a mixture of enantiomercompounds 5′ (R,S) and 6′ (R,R) can be prepared from (R) compound 11″.

Alternately, compound 11 can be reduced using asymmetric conditions toprepare a mixture of compounds 5 (S,R) and 6 (R,R) which can beseparated by silica or reverse phase chromatography to yieldenantiomerically pure compounds 5 and 6. The asymmetric reduction of theketone may be carried out using the appropriate chiral reagents such asCorey-Bakshi-Shibata (CBS) catalyst, asymmetric hydrogenation orasymmetric transfer hydrogenation with the appropriate chiral ligand.See, for example, Corey et al. (1988) J. Org, Chem. 53:2861-2863.

Similarly, the single compound 5 (S,R) or the single compound 6 (S,S)may be synthesized from the (S) compound 11′ and a chiral asymmetricreduction using the appropriate chiral reagents. Likewise, the singlecompound 5′ (R,S) or the single compound 6′ (R,R) may be synthesizedfrom the (R) compound 11″ and a chiral asymmetric reduction using theappropriate chiral reagents.

If desired, pharmaceutically acceptable salts of the compounds offormula I can be prepared by contacting the free acid or base form of acompound of formula I with a pharmaceutically acceptable base or acid.

Certain of the intermediates described herein are believed to be noveland accordingly, such compounds are provided as further aspects of theinvention including, for example, compounds 8 and 8′:

where P represents an amino-protecting group, particularlyt-butoxycarbonyl (BOC). In one embodiment of the invention, compounds ofthe invention can be prepared by deprotecting a compound of the formula:

where P represents an amino-protecting group, to provide a compound offormula I, or a salt thereof. In one particular embodiment, suchunprotected compounds have the formula of compounds 8 or 8′.

Further details regarding specific reaction conditions and otherprocedures for preparing representative compounds of the invention orintermediates thereof are described in the Examples set forth herein.

Utility

Compounds of the invention possess serotonin and norepinephrine reuptakeinhibitory activity, and in one embodiment, at nanomolar potencies.Thus, these compounds have therapeutic utility as combined serotonin andnorepinephrine reuptake inhibitors (SNRIs). In one embodiment, compoundsof the invention are equipotent at both targets, i.e., possessapproximately equal serotonin reuptake inhibitory activity andnorepinephrine reuptake inhibitory activity.

The inhibition constant (K_(i)) of a compound is the concentration ofcompeting ligand in a competition assay that would occupy 50% of thetransporters if no radioligand were present. K_(i) values can bedetermined from radioligand competition binding studies with³H-nisoxetine (for the norepinephrine transporter, NET) and³H-citalopram (for the serotonin transporter, SERT), as described inAssay 1. These K_(i) values are derived from IC₅₀ values in the bindingassay using the Cheng-Prusoff equation and the K_(d) of the radioligand(Cheng & Prusoff (1973) Biochem. Pharmacol. 22(23):3099-3108).Functional IC₅₀ values can be determined in the functional inhibition ofuptake assays described in Assay 2. These IC₅₀ values can be convertedto K_(i) values using the Cheng-Prusoff equation and the K_(m) of thetransmitter for the transporter. It is noted however, that the uptakeassay conditions described in Assay 2 are such that the IC₅₀ values arevery close to the K_(i) values, should a mathematical conversion bedesired, since the neurotransmitter concentration (5-HT or NE) used inthe assay is well below its K_(m) for the respective transporter.

One measure of the affinity of a compound for SERT or NET is theinhibitory constant (pK_(i)) for binding to the transporter. The pK_(i)value is the negative logarithm to base 10 of the K_(i). Compounds ofthe invention of particular interest are those having a pK_(i) at SERTgreater than or equal to 7.5. Compounds of the invention of particularinterest also include those having a pK_(i) at NET greater than or equalto 7.0. In another embodiment, compounds of interest have a pK_(i) atNET greater than or equal to 8.0, and in yet another embodiment,compounds of interest have a pK_(i) at NET within the range of 8.0 to9.0. In one embodiment, compounds of interest have a pK_(i) at SERT andat NET of greater than or equal to 7.5. In another embodiment, compoundsof interest have a pK_(i) at SERT and at NET greater than or equal to8.0. Such values can be determined by techniques that are well know inthe art, as well as in the assays described herein.

In one embodiment, compounds of the invention exhibit a NET pK_(i)≧8 anda SERT K_(i)/NET K_(i) in the range of 0.1 to 100; and in otherembodiments, exhibit a SERT K_(i)/NET K_(i) in the range of 0.3 to 100,0.3 to 10, or 0.1 to 30. In another embodiment, compounds of theinvention exhibit a NET pK_(i)≧9 and a SERT K_(i)/NET K_(i) in the rangeof 0.1 to 100; and in others embodiment, exhibit a SERT K_(i)/NET K_(i)in the range of 0.3 to 100, 0.3 to 10, or 0.1 to 30.

Another measure of serotonin and norepinephrine reuptake inhibition isthe pIC₅₀ value. In one embodiment, compounds of interest are thosehaving a serotonin reuptake inhibition pIC₅₀ value greater than or equalto 7.5. Compounds of the invention of particular interest also includethose having a norepinephrine reuptake inhibition pIC₅₀ value greaterthan or equal to 7.0. In another embodiment, compounds of interest havea norepinephrine reuptake inhibition pIC₅₀ value greater than or equalto 8.0, and in yet another embodiment, compounds of interest have anorepinephrine reuptake inhibition pIC₅₀ value within the range of 8.0to 9.0. In one embodiment, compounds of interest have a serotoninreuptake inhibition pIC₅₀ value and a norepinephrine reuptake inhibitionpIC₅₀ value of greater than or equal to 7.5. In another embodiment,compounds of interest have a serotonin reuptake inhibition pIC₅₀ valueand a norepinephrine reuptake inhibition pIC₅₀ value greater than orequal to 8.0. In one particular embodiment, the compounds of theinvention have balanced pIC₅₀ values.

In another embodiment, compounds of the invention are selective forinhibition of SERT and NET over the dopamine transporter (DAT). Forexample in this embodiment, compounds of particular interest are thosethat exhibit a binding affinity for SERT and NET that is at least 5times higher than the binding affinity for DAT, or that is at least 10times higher than for DAT, or at least 20 or 30 times higher than forDAT. In another embodiment, the compounds do not exhibit significant DATinhibition. In still another embodiment, the compounds exhibit less than50% inhibition of DAT activity when measured at a concentration of 794nM. Under the assay conditions used, a compound which exhibits ≦50%inhibition would have an estimated pK_(i) value at DAT of ≦6.1.

In still another embodiment, compounds of the invention possess dopaminereuptake inhibitory activity as well as serotonin and norepinephrinereuptake inhibitory activity. For example in this embodiment, compoundsof particular interest are those that exhibit a pK_(i) at SERT and NETgreater than or equal to 8.0, and a pK_(i) at DAT greater than or equalto 7.0.

It is noted that in some cases, compounds of the invention may possesseither weak serotonin reuptake inhibitory activity or weaknorepinephrine reuptake inhibitory activity. In these cases, those ofordinary skill in the art will recognize that such compounds still haveutility as primarily either a NET inhibitor or a SERT inhibitor,respectively, or will have utility as research tools.

Exemplary assays to determine the serotonin and/or norepinephrinereuptake inhibiting activity of compounds of the invention include byway of illustration and not limitation, assays that measure SERT and NETbinding, for example, as described in Assay 1. In addition, it is usefulto understand the level of DAT binding and uptake in an assay such asthat described in Assay 1. Useful secondary assays includeneurotransmitter uptake assays to measure competitive inhibition ofserotonin and norepinephrine uptake into cells expressing the respectivehuman or rat recombinant transporter (hSERT, hNET, or hDAT) as describedin Assay 2, and ex vivo radioligand binding and neurotransmitter uptakeassays that are used to determine the in vivo occupancy of SERT, NET andDAT in tissue as described in Assay 3. Other assays that are useful toevaluate pharmacological properties of test compounds include thoselisted in Assay 4. Exemplary in vivo assays include the formalin pawtest described in Assay 5, which is a reliable predictor of clinicalefficacy for the treatment of neuropathic pain, and the spinal nerveligation model described in Assay 6. The aforementioned assays areuseful in determining the therapeutic utility, for example, theneuropathic pain relieving activity, of compounds of the invention.Other properties and utilities of compounds of the invention can bedemonstrated using various in vitro and in vivo assays well-known tothose skilled in the art.

Compounds of the invention are expected to be useful for the treatmentand/or prevention of medical conditions in which the regulation ofmonoamine transporter function is implicated, in particular thoseconditions mediated by or responsive to the inhibition of serotonin andnorepinephrine reuptake. Thus it is expected that patients sufferingfrom a disease or disorder that is treated by the inhibition of theserotonin and/or the norepinephrine transporter can be treated byadministering a therapeutically effective amount of a serotonin andnorepinephrine reuptake inhibitor of the invention. Such medicalconditions include, by way of example, pain disorders such asneuropathic pain and chronic pain, depressive disorders such as majordepression, affective disorders such as an anxiety disorder, attentiondeficit hyperactivity disorder, cognitive disorders such as dementia,and stress urinary incontinence.

The amount of active agent administered per dose or the total amountadministered per day may be predetermined or it may be determined on anindividual patient basis by taking into consideration numerous factors,including the nature and severity of the patient's condition, thecondition being treated, the age, weight, and general health of thepatient, the tolerance of the patient to the active agent, the route ofadministration, pharmacological considerations such as the activity,efficacy, pharmacokinetics and toxicology profiles of the active agentand any secondary agents being administered, and the like. Treatment ofa patient suffering from a disease or medical condition (such asneuropathic pain) can begin with a predetermined dosage or a dosagedetermined by the treating physician, and will continue for a period oftime necessary to prevent, ameliorate, suppress, or alleviate thesymptoms of the disease or medical condition. Patients undergoing suchtreatment will typically be monitored on a routine basis to determinethe effectiveness of therapy. For example, in treating neuropathic pain,a measure of the effectiveness of treatment may involve assessment ofthe patient's quality of life, e.g., improvements in the patient'ssleeping patterns, work attendance, ability to exercise and beambulatory, etc. Pain scales, operating on a point basis, may also beused to help evaluate a patient's pain level. Indicators for the otherdiseases and conditions described herein, are well-known to thoseskilled in the art, and are readily available to the treating physician.Continuous monitoring by the physician will ensure that the optimalamount of active agent will be administered at any given time, as wellas facilitating the determination of the duration of treatment. This isof particular value when secondary agents are also being administered,as their selection, dosage, and duration of therapy may also requireadjustment. In this way, the treatment regimen and dosing schedule canbe adjusted over the course of therapy so that the lowest amount ofactive agent that exhibits the desired effectiveness is administeredand, further, that administration is continued only so long as isnecessary to successfully treat the disease or medical condition.

Pain Disorders

SNRIs have been shown to have a beneficial effect on pain such aspainful diabetic neuropathy (duloxetine, Goldstein et al. (2005) Pain116:109-118; venlafaxine, Rowbotham et al. (2004) Pain 110:697-706),fibromyalgia (duloxetine, Russell et al (2008) Pain 136(3):432-444;milnacipran, Vitton et al. (2004) Human Psychopharmacology 19:S27-S35),and migraine (venlafaxine, Ozyalcin et al. (2005) Headache45(2):144-152). Thus, one embodiment of the invention relates to amethod for treating a pain disorder, comprising administering to apatient a therapeutically effective amount of a compound of theinvention. Typically, the therapeutically effective amount will be theamount that is sufficient to relieve the pain. Exemplary pain disordersinclude, by way of illustration, acute pain, persistent pain, chronicpain, inflammatory pain, and neuropathic pain. More specifically, theseinclude pain associated with or caused by: arthritis; back painincluding chronic low back pain; cancer, including tumor related pain(e.g. bone pain, headache, facial pain or visceral pain) and painassociated with cancer therapy (e.g. post-chemotherapy syndrome, chronicpost-surgical pain syndrome and post-radiation syndrome); carpal tunnelsyndrome; fibromyalgia; headaches including chronic tension headaches;inflammation associated with polymyalgia, rheumatoid arthritis andosteoarthritis; migraine; neuropathic pain including complex regionalpain syndrome; overall pain; post-operative pain; shoulder pain; centralpain syndromes, including post-stroke pain, and pain associated withspinal cord injuries and multiple sclerosis; phantom limb pain; painassociated with Parkinson's disease; and visceral pain (e.g., irritablebowel syndrome). Of particular interest is the treatment of neuropathicpain, which includes diabetic peripheral neuropathy (DPN), HIV-relatedneuropathy, post-herpetic neuralgia (PHN), and chemotherapy-inducedperipheral neuropathy. When used to treat pain disorders such asneuropathic pain, compounds of the invention may be administered incombination with other therapeutic agents, including anticonvulsants,antidepressants, muscle relaxants, NSAIDs, opioid agonists, selectiveserotonin reuptake inhibitors, sodium channel blockers, andsympatholytics. Exemplary compounds within these classes are describedherein.

Depressive Disorders

Another embodiment of the invention relates to a method of treating adepressive disorder, comprising administering to a patient atherapeutically effective amount of a compound of the invention.Typically, the therapeutically effective amount will be the amount thatis sufficient to alleviate depression and provide a sense of generalwell-being. Exemplary depressive disorders include, by way ofillustration and not limitation: depression associated with Alzheimer'sdisease, bipolar disorder, cancer, child abuse, infertility, Parkinson'sdisease, postmyocardial infarction, and psychosis; dysthymia; grumpy orirritable old man syndrome; induced depression; major depression;pediatric depression; postmenopausal depression; post partum depression;recurrent depression; single episode depression; and subsyndromalsymptomatic depression. Of particular interest is the treatment of majordepression. When used to treat depressive disorders, compounds of theinvention may be administered in combination with other therapeuticagents, including antidepressants and dual serotonin-norepinephrinereuptake inhibitors. Exemplary compounds within these classes aredescribed herein.

Affective Disorders

Another embodiment of the invention relates to a method of treating anaffective disorder, comprising administering to a patient atherapeutically effective amount of a compound of the invention.Exemplary affective disorders include, by way of illustration and notlimitation: anxiety disorders such as general anxiety disorder; avoidantpersonality disorder; eating disorders such as anorexia nervosa, bulimianervosa and obesity; obsessive compulsive disorder; panic disorder;personality disorders such as avoidant personality disorder andattention deficit hyperactivity disorder (ADHD); post-traumatic stresssyndrome; phobias such as agoraphobia, as well as simple and otherspecific phobias, and social phobia; premenstrual syndrome; psychoticdisorders, such as schizophrenia and mania; seasonal affective disorder;sexual dysfunction, including premature ejaculation, male impotence, andfemale sexual dysfunction such as female sexual arousal disorder; socialanxiety disorder; and substance abuse disorders, including chemicaldependencies such as addictions to alcohol, benzodiazepines, cocaine,heroin, nicotine and phenobarbital, as well as withdrawal syndromes thatmay arise from these dependencies. When used to treat affectivedisorders, compounds of the invention may be administered in combinationwith other therapeutic agents, including antidepressants. Exemplarycompounds within these classes are described herein.

Atomoxetine, which is 10-fold NET selective, is approved for attentiondeficit hyperactivity disorder (ADHD) therapy, and clinical studies haveshown that the SNRI, venlafaxine, can also have a beneficial effect intreating ADHD (Mukaddes et al. (2002) Eur. Neuropsychopharm. 12(Supp3):421). Thus, the compounds of the invention are also expected to beuseful in methods for treating attention deficit hyperactivity disorderby administering to a patient a therapeutically effective amount of acompound of the invention. When used to treat depression, compounds ofthe invention may be administered in combination with other therapeuticagents, including antidepressants. Exemplary compounds within theseclasses are described herein.

Cognitive Disorders

Another embodiment of the invention relates to a method of treating acognitive disorder, comprising administering to a patient atherapeutically effective amount of a compound of the invention.Exemplary cognitive disorders include, by way of illustration and notlimitation: dementia, which includes degenerative dementia (e.g.,Alzheimer's disease, Creutzfeldt-Jakob disease, Huntingdon's chorea,Parkinson's disease, Pick's disease, and senile dementia), vasculardementia (e.g., multi-infarct dementia), and dementia associated withintracranial space occupying lesions, trauma, infections and relatedconditions (including HIV infection), metabolism, toxins, anoxia andvitamin deficiency; and mild cognitive impairment associated with aging,such as age associated memory impairment, amnesiac disorder andage-related cognitive decline. When used to treat cognitive disorders,compounds of the invention may be administered in combination with othertherapeutic agents, including anti-Alzheimer's agents andanti-Parkinson's agents. Exemplary compounds within these classes aredescribed herein.

Other Disorders

SNRIs have also been shown to be effective for the treatment of stressurinary incontinence (Dmochowski (2003) Journal of Urology 170(4):1259-1263). Thus, another embodiment of the invention relates to amethod for treating stress urinary incontinence, comprisingadministering to a patient a therapeutically effective amount of acompound of the invention. When used to treat stress urinaryincontinence, compounds of the invention may be administered incombination with other therapeutic agents, including anticonvulsants.Exemplary compounds within these classes are described herein.

Duloxetine, an SNRI, is undergoing clinical trials for evaluating itsefficacy in treating chronic fatigue syndrome, and has recently beenshown to be effective in treating fibromyalgia (Russell et al (2008)Pain 136(3):432-444). The compounds of the invention, due to theirability to inhibit SERT and NET, are also expected to have this utility,and another embodiment of the invention relates to a method for treatingchronic fatigue syndrome, comprising administering to a patient atherapeutically effective amount of a compound of the invention.

Sibutramine, a norepinephrine and dopamine reuptake inhibitor, has beenshown to be useful in treating obesity (Wirth et al. (2001) JAMA286(11):1331-1339). The compounds of the invention, due to their abilityto inhibit NET, are also expected to have this utility, and anotherembodiment of the invention relates to a method for treating obesity,comprising administering to a patient a therapeutically effective amountof a compound of the invention.

Desvenlafaxine, an SNRI, has been shown to relieve vasomotor symptomsassociated with menopause (Deecher et al. (2007) Endocrinology148(3):1376-1383). The compounds of the invention, due to their abilityto inhibit SERT and NET, are also expected to have this utility, andanother embodiment of the invention relates to a method for treatingvasomotor symptoms associated with menopause, comprising administeringto a patient a therapeutically effective amount of a compound of theinvention.

Research Tools

Since compounds of the invention possess both serotonin reuptakeinhibition activity and norepinephrine reuptake inhibition activity,such compounds are also useful as research tools for investigating orstudying biological systems or samples having serotonin ornorepinephrine transporters. Any suitable biological system or samplehaving serotonin and/or norepinephrine transporters may be employed insuch studies which may be conducted either in vitro or in vivo.Representative biological systems or samples suitable for such studiesinclude, but are not limited to, cells, cellular extracts, plasmamembranes, tissue samples, isolated organs, mammals (such as mice, rats,guinea pigs, rabbits, dogs, pigs, humans, and so forth), and the like,with mammals being of particular interest. In one particular embodimentof the invention, serotonin reuptake in a mammal is inhibited byadministering a serotonin reuptake-inhibiting amount of a compound ofthe invention. In another particular embodiment, norepinephrine reuptakein a mammal is inhibited by administering a norepinephrinereuptake-inhibiting amount of a compound of the invention. Compounds ofthe invention can also be used as research tools by conductingbiological assays using such compounds.

When used as a research tool, a biological system or sample comprising aserotonin transporter and/or a norepinephrine transporter is typicallycontacted with a serotonin reuptake-inhibiting or norepinephrinereuptake-inhibiting amount of a compound of the invention. After thebiological system or sample is exposed to the compound, the effects ofinhibiting serotonin reuptake and/or norepinephrine reuptake aredetermined using conventional procedures and equipment. Exposureencompasses contacting cells or tissue with the compound, administeringthe compound to a mammal, for example by i.p. or i.v. administration,and so forth. This determining step may comprise measuring a response,i.e., a quantitative analysis or may comprise an observation, i.e., aqualitative analysis. Measuring a response involves, for example,determining the effects of the compound on the biological system orsample using conventional procedures and equipment, such as serotoninand norepinephrine reuptake assays. The assay results can be used todetermine the activity level as well as the amount of compound necessaryto achieve the desired result, i.e., a serotonin reuptake-inhibiting anda norepinephrine reuptake-inhibiting amount.

Additionally, compounds of the invention can be used as research toolsfor evaluating other chemical compounds, and thus are also useful inscreening assays to discover, for example, new compounds having bothserotonin reuptake-inhibiting activity and norepinephrinereuptake-inhibiting activity. In this manner, a compound of theinvention is used as a standard in an assay to allow comparison of theresults obtained with a test compound and with compounds of theinvention to identify those test compounds that have about equal orsuperior reuptake-inhibiting activity, if any. For example, reuptakedata for a test compound or a group of test compounds is compared to thereuptake data for a compound of the invention to identify those testcompounds that have the desired properties, e.g., test compounds havingreuptake-inhibiting activity about equal or superior to a compound ofthe invention, if any. This aspect of the invention includes, asseparate embodiments, both the generation of comparison data (using theappropriate assays) and the analysis of the test data to identify testcompounds of interest. Thus, a test compound can be evaluated in abiological assay, by a method comprising the steps of: (a) conducting abiological assay with a test compound to provide a first assay value;(b) conducting the biological assay with a compound of the invention toprovide a second assay value; wherein step (a) is conducted eitherbefore, after or concurrently with step (b); and (c) comparing the firstassay value from step (a) with the second assay value from step (b).Exemplary biological assays include serotonin and norepinephrinereuptake assays.

Pharmaceutical Compositions and Formulations

Compounds of the invention are typically administered to a patient inthe form of a pharmaceutical composition or formulation. Suchpharmaceutical compositions may be administered to the patient by anyacceptable route of administration including, but not limited to, oral,rectal, vaginal, nasal, inhaled, topical (including transdermal) andparenteral modes of administration. Further, the compounds of theinvention may be administered, for example orally, in multiple doses perday (e.g. twice, three times or four times daily), in a single dailydose, in a twice-daily dose, in a single weekly dose, and so forth. Itwill be understood that any form of the compounds of the invention,(i.e., free base, pharmaceutically acceptable salt, solvate, etc.) thatis suitable for the particular mode of administration can be used in thepharmaceutical compositions discussed herein.

Accordingly, in one embodiment, the invention relates to apharmaceutical composition comprising a pharmaceutically acceptablecarrier and a compound of the invention. The compositions may containother therapeutic and/or formulating agents if desired. When discussingcompositions, the “compound of the invention” may also be referred toherein as the “active agent,” to distinguish it from other components ofthe formulation, such as the carrier. Thus, it is understood that theterm “active agent” includes compounds of formula I as well aspharmaceutically acceptable salts and solvates of that compound.

The pharmaceutical compositions of the invention typically contain atherapeutically effective amount of a compound of the invention. Thoseskilled in the art will recognize, however, that a pharmaceuticalcomposition may contain more than a therapeutically effective amount,i.e., bulk compositions, or less than a therapeutically effectiveamount, i.e., individual unit doses designed for multiple administrationto achieve a therapeutically effective amount. Typically, thecomposition will contain from about 0.01-95 wt % of active agent,including, from about 0.01-30 wt %, such as from about 0.01-10 wt %,with the actual amount depending upon the formulation itself, the routeof administration, the frequency of dosing, and so forth. In oneembodiment, a composition suitable for an oral dosage form, for example,may contain about 5-70 wt %, or from about 10-60 wt % of active agent.

Any conventional carrier or excipient may be used in the pharmaceuticalcompositions of the invention. The choice of a particular carrier orexcipient, or combinations of carriers or excipients, will depend on themode of administration being used to treat a particular patient or typeof medical condition or disease state. In this regard, the preparationof a suitable composition for a particular mode of administration iswell within the scope of those skilled in the pharmaceutical arts.Additionally, carriers or excipients used in such compositions arecommercially available. By way of further illustration, conventionalformulation techniques are described in Remington: The Science andPractice of Pharmacy, 20^(th) Edition, Lippincott Williams & White,Baltimore, Md. (2000); and H. C. Ansel et al., Pharmaceutical DosageForms and Drug Delivery Systems, 7^(th) Edition, Lippincott Williams &White, Baltimore, Md. (1999).

Representative examples of materials which can serve as pharmaceuticallyacceptable carriers include, but are not limited to, the following:sugars, such as lactose, glucose and sucrose; starches, such as cornstarch and potato starch; cellulose, such as microcrystalline cellulose,and its derivatives, such as sodium carboxymethyl cellulose, ethylcellulose and cellulose acetate; powdered tragacanth; malt; gelatin;talc; excipients, such as cocoa butter and suppository waxes; oils, suchas peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil,corn oil and soybean oil; glycols, such as propylene glycol; polyols,such as glycerin, sorbitol, mannitol and polyethylene glycol; esters,such as ethyl oleate and ethyl laurate; agar; buffering agents, such asmagnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-freewater; isotonic saline; Ringer's solution; ethyl alcohol; phosphatebuffer solutions; compressed propellant gases, such aschlorofluorocarbons and hydrofluorocarbons; and other non-toxiccompatible substances employed in pharmaceutical compositions.

Pharmaceutical compositions are typically prepared by thoroughly andintimately mixing or blending the active agent with a pharmaceuticallyacceptable carrier and one or more optional ingredients. The resultinguniformly blended mixture may then be shaped or loaded into tablets,capsules, pills, canisters, cartridges, dispensers, and the like, usingconventional procedures and equipment.

In one embodiment, the pharmaceutical compositions are suitable for oraladministration. One exemplary dosing regimen would be an oral dosageform administered once or twice daily. Suitable compositions for oraladministration may be in the form of capsules, tablets, pills, lozenges,cachets, dragees, powders, granules; solutions or suspensions in anaqueous or non-aqueous liquid; oil-in-water or water-in-oil liquidemulsions; elixirs or syrups; and the like; each containing apredetermined amount of the active agent.

When intended for oral administration in a solid dosage form (i.e., ascapsules, tablets, pills, and the like), the composition will typicallycomprise the active agent and one or more pharmaceutically acceptablecarriers, such as sodium citrate or dicalcium phosphate. Solid dosageforms may also comprise: fillers or extenders, such as starches,microcrystalline cellulose, lactose, sucrose, glucose, mannitol, and/orsilicic acid; binders, such as carboxymethylcellulose, alginates,gelatin, polyvinyl pyrrolidone, sucrose and/or acacia; humectants, suchas glycerol; disintegrating agents, such as agar-agar, calciumcarbonate, potato or tapioca starch, alginic acid, certain silicates,and/or sodium carbonate; solution retarding agents, such as paraffin;absorption accelerators, such as quaternary ammonium compounds; wettingagents, such as cetyl alcohol and/or glycerol monostearate; absorbents,such as kaolin and/or bentonite clay; lubricants, such as talc, calciumstearate, magnesium stearate, solid polyethylene glycols, sodium laurylsulfate, and/or mixtures thereof, coloring agents; and buffering agents.

Release agents, wetting agents, coating agents, sweetening, flavoringand perfuming agents, preservatives and antioxidants may also be presentin the pharmaceutical compositions. Exemplary coating agents fortablets, capsules, pills and like, include those used for entericcoatings, such as cellulose acetate phthalate, polyvinyl acetatephthalate, hydroxypropyl methylcellulose phthalate, methacrylicacid-methacrylic acid ester copolymers, cellulose acetate trimellitate,carboxymethyl ethyl cellulose, hydroxypropyl methyl cellulose acetatesuccinate, and the like. Examples of pharmaceutically acceptableantioxidants include: water-soluble antioxidants, such as ascorbic acid,cysteine hydrochloride, sodium bisulfate, sodium metabisulfate, sodiumsulfite and the like; oil-soluble antioxidants, such as ascorbylpalmitate, butylated hydroxyanisole, butylated hydroxytoluene, lecithin,propyl gallate, alpha-tocopherol, and the like; and metal-chelatingagents, such as citric acid, ethylenediamine tetraacetic acid, sorbitol,tartaric acid, phosphoric acid, and the like.

Compositions may also be formulated to provide slow or controlledrelease of the active agent using, by way of example, hydroxypropylmethyl cellulose in varying proportions or other polymer matrices,liposomes and/or microspheres. In addition, the pharmaceuticalcompositions of the invention may contain opacifying agents and may beformulated so that they release the active agent only, orpreferentially, in a certain portion of the gastrointestinal tract,optionally, in a delayed manner. Examples of embedding compositionswhich can be used include polymeric substances and waxes. The activeagent can also be in micro-encapsulated form, if appropriate, with oneor more of the above-described excipients.

Suitable liquid dosage forms for oral administration include, by way ofillustration, pharmaceutically acceptable emulsions, microemulsions,solutions, suspensions, syrups and elixirs. Liquid dosage formstypically comprise the active agent and an inert diluent, such as, forexample, water or other solvents, solubilizing agents and emulsifiers,such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethylacetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butyleneglycol, oils (e.g., cottonseed, groundnut, corn, germ, olive, castor andsesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycolsand fatty acid esters of sorbitan, and mixtures thereof. Suspensions maycontain suspending agents such as, for example, ethoxylated isostearylalcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystallinecellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth,and mixtures thereof.

When intended for oral administration, the pharmaceutical compositionsof the invention may be packaged in a unit dosage form. The term “unitdosage form” refers to a physically discrete unit suitable for dosing apatient, i.e., each unit containing a predetermined quantity of theactive agent calculated to produce the desired therapeutic effect eitheralone or in combination with one or more additional units. For example,such unit dosage forms may be capsules, tablets, pills, and the like.

In another embodiment, the compositions of the invention are suitablefor inhaled administration, and will typically be in the form of anaerosol or a powder. Such compositions are generally administered usingwell-known delivery devices, such as a nebulizer, dry powder, ormetered-dose inhaler. Nebulizer devices produce a stream of highvelocity air that causes the composition to spray as a mist that iscarried into a patient's respiratory tract. An exemplary nebulizerformulation comprises the active agent dissolved in a carrier to form asolution, or micronized and combined with a carrier to form a suspensionof micronized particles of respirable size. Dry powder inhalersadminister the active agent as a free-flowing powder that is dispersedin a patient's air-stream during inspiration. An exemplary dry powderformulation comprises the active agent dry-blended with an excipientsuch as lactose, starch, mannitol, dextrose, polylactic acid,polylactide-co-glycolide, and combinations thereof. Metered-doseinhalers discharge a measured amount of the active agent usingcompressed propellant gas. An exemplary metered-dose formulationcomprises a solution or suspension of the active agent in a liquefiedpropellant, such as a chlorofluorocarbon or hydrofluoroalkane. Optionalcomponents of such formulations include co-solvents, such as ethanol orpentane, and surfactants, such as sorbitan trioleate, oleic acid,lecithin, and glycerin. Such compositions are typically prepared byadding chilled or pressurized hydrofluoroalkane to a suitable containercontaining the active agent, ethanol (if present) and the surfactant (ifpresent). To prepare a suspension, the active agent is micronized andthen combined with the propellant. Alternatively, a suspensionformulation can be prepared by spray drying a coating of surfactant onmicronized particles of the active agent. The formulation is then loadedinto an aerosol canister, which forms a portion of the inhaler.

Compounds of the invention can also be administered parenterally (e.g.,by subcutaneous, intravenous, intramuscular, or intraperitonealinjection). For such administration, the active agent is provided in asterile solution, suspension, or emulsion. Exemplary solvents forpreparing such formulations include water, saline, low molecular weightalcohols such as propylene glycol, polyethylene glycol, oils, gelatin,fatty acid esters such as ethyl oleate, and the like. A typicalparenteral formulation is a sterile pH 4-7 aqueous solution of theactive agent. Parenteral formulations may also contain one or moresolubilizers, stabilizers, preservatives, wetting agents, emulsifiers,and dispersing agents. These formulations may be rendered sterile by useof a sterile injectable medium, a sterilizing agent, filtration,irradiation, or heat.

Compounds of the invention can also be administered transdermally usingknown transdermal delivery systems and excipients. For example, thecompound can be admixed with permeation enhancers, such as propyleneglycol, polyethylene glycol monolaurate, azacycloalkan-2-ones and thelike, and incorporated into a patch or similar delivery system.Additional excipients including gelling agents, emulsifiers and buffers,may be used in such transdermal compositions if desired.

If desired, compounds of the invention may be administered incombination with one or more other therapeutic agents. Thus, in oneembodiment, compositions of the invention may optionally contain otherdrugs that are co-administered with a compound of the invention. Forexample, the composition may further comprise one or more drugs (alsoreferred to as “secondary agents(s)”) selected from the group ofanti-Alzheimer's agents, anticonvulsants (antiepileptics),antidepressants, anti-Parkinson's agents, dual serotonin-norepinephrinereuptake inhibitors (SNRIs), non-steroidal anti-inflammatory agents(NSAIDs), norepinephrine reuptake inhibitors, opioid agonists (opioidanalgesics), selective serotonin reuptake inhibitors, sodium channelblockers, sympatholytics, and combinations thereof. Numerous examples ofsuch therapeutic agents are well known in the art, and examples aredescribed herein. By combining a compound of the invention with asecondary agent, triple therapy can be achieved, i.e., serotoninreuptake inhibitory activity, norepinephrine reuptake inhibitoryactivity, and activity associated with the secondary agent (e.g.,antidepressant activity), using only two active components. Sincepharmaceutical compositions containing two active components aretypically easier to formulate than compositions containing three activecomponents, such two-component compositions provide a significantadvantage over compositions containing three active components.Accordingly, in yet another aspect of the invention, a pharmaceuticalcomposition comprises a compound of the invention, a second activeagent, and a pharmaceutically acceptable carrier. Third, fourth etc.active agents may also be included in the composition. In combinationtherapy, the amount of compound of the invention that is administered,as well as the amount of secondary agents, may be less than the amounttypically administered in monotherapy.

A compound of the invention may be either physically mixed with thesecond active agent to form a composition containing both agents; oreach agent may be present in separate and distinct compositions whichare administered to the patient simultaneously or sequentially. Forexample, a compound of the invention can be combined with a secondactive agent using conventional procedures and equipment to form acombination of active agents comprising a compound of the invention anda second active agent. Additionally, the active agents may be combinedwith a pharmaceutically acceptable carrier to form a pharmaceuticalcomposition comprising a compound of the invention, a second activeagent and a pharmaceutically acceptable carrier. In this embodiment, thecomponents of the composition are typically mixed or blended to create aphysical mixture. The physical mixture is then administered in atherapeutically effective amount using any of the routes describedherein.

Alternatively, the active agents may remain separate and distinct beforeadministration to the patient. In this embodiment, the agents are notphysically mixed together before administration but are administeredsimultaneously or at separate times as separate compositions. Suchcompositions can be packaged separately or may be packaged together in akit. When administered at separate times, the secondary agent willtypically be administered less than 24 hours after administration of thecompound of the invention, ranging anywhere from concurrent withadministration of the compound of the invention to about 24 hourspost-dose. This is also referred to as sequential administration. Thus,a compound of the invention can be orally administered simultaneously orsequentially with another active agent using two tablets, with onetablet for each active agent, where sequential may mean beingadministered immediately after administration of the compound of theinvention or at some predetermined time later (e.g., one hour later orthree hours later). Alternatively, the combination may be administeredby different routes of administration, i.e., one orally and the other byinhalation.

In one embodiment, the kit comprises a first dosage form comprising acompound of the invention and at least one additional dosage formcomprising one or more of the secondary agents set forth herein, inquantities sufficient to carry out the methods of the invention. Thefirst dosage form and the second (or third, etc,) dosage form togethercomprise a therapeutically effective amount of active agents for thetreatment or prevention of a disease or medical condition in a patient.

Secondary agent(s), when included, are present in a therapeuticallyeffective amount. i.e., are typically administered in an amount thatproduces a therapeutically beneficial effect when co-administered with acompound of the invention. The secondary agent can be in the form of apharmaceutically acceptable salt, solvate, optically pure stereoisomer,and so forth. Thus, secondary agents listed below are intended toinclude all such forms, and are commercially available or can beprepared using conventional procedures and reagents.

Representative anti-Alzheimer's agents include, but are not limited to:donepezil, galantamine, memantine, rivastigmine, selegiline, tacrine,and combinations thereof.

Representative anticonvulsants (antiepileptics) include, but are notlimited to: acetazolamide, albutoin, 4-amino-3-hydroxybutyric acid,beclamide, carbamazepine, cinromide, clomethiazole, clonazepam,diazepam, dimethadione, eterobarb, ethadione, ethosuximide, ethotoin,felbamate, fosphenytoin, gabapentin, lacosamide, lamotrigine, lorazepam,magnesium bromide, magnesium sulfate, mephenytoin, mephobarbital,methsuximide, midazolam, nitrazepam, oxazepam, oxcarbazepine,paramethadione, phenacemide, pheneturide, phenobarbital, phensuximide,phenytoin, potassium bromide, pregabalin, primidone, progabide, sodiumbromide, sodium valproate, sulthiame, tiagabine, topiramate,trimethadione, valproic acid, valpromide, vigabatrin, zonisamide, andcombinations thereof. In a particular embodiment, the anticonvulsant isselected from carbamazepine, gabapentin, pregabalin, and combinationsthereof.

Representative antidepressants include, but are not limited to:adinazolam, amitriptyline, clomipramine, desipramine, dothiepin (e.g.,dothiepin hydrochloride), doxepin, imipramine, lofepramine, mirtazapine,nortriptyline, protriptyline, trimipramine, venlafaxine, zimelidine, andcombinations thereof.

Representative anti-Parkinson's agents include, but are not limited to:amantadine, apomorphine, benztropine, bromocriptine, carbidopa,diphenhydramine, entacapone, levodopa, pergolide, pramipexole,ropinirole, selegiline, tolcapone, trihexyphenidyl, and combinationsthereof.

Representative dual serotonin-norepinephrine reuptake inhibitors (SNRIs)include, but are not limited to: bicifadine, desvenlafaxine, duloxetine,milnacipran, nefazodone, venlafaxine, and combinations thereof.

Representative non-steroidal anti-inflammatory agents (NSAIDs) include,but are not limited to: acemetacin, acetaminophen, acetyl salicylicacid, alclofenac, alminoprofen, amfenac, amiprilose, amoxiprin,anirolac, apazone, azapropazone, benorilate, benoxaprofen, bezpiperylon,broperamole, bucloxic acid, carprofen, clidanac, diclofenac, diflunisal,diftalone, enolicam, etodolac, etoricoxib, fenbufen, fenclofenac,fenclozic acid, fenoprofen, fentiazac, feprazone, flufenamic acid,flufenisal, fluprofen, flurbiprofen, furofenac, ibufenac, ibuprofen,indomethacin, indoprofen, isoxepac, isoxicam, ketoprofen, ketorolac,lofemizole, lornoxicam, meclofenamate, meclofenamic acid, mefenamicacid, meloxicam, mesalamine, miroprofen, mofebutazone, nabumetone,naproxen, niflumic acid, nimesulide, nitroflurbiprofen, olsalazine,oxaprozin, oxpinac, oxyphenbutazone, phenylbutazone, piroxicam,pirprofen, pranoprofen, salsalate, sudoxicam, sulfasalazine, sulindac,suprofen, tenoxicam, tiopinac, tiaprofenic acid, tioxaprofen, tolfenamicacid, tolmetin, triflumidate, zidometacin, zomepirac, and combinationsthereof. In a particular embodiment, the NSAID is selected frometodolac, flurbiprofen, ibuprofen, indomethacin, ketoprofen, ketorolac,meloxicam, naproxen, oxaprozin, piroxicam, and combinations thereof In aparticular embodiment, the NSAID is selected from ibuprofen,indomethacin, nabumetone, naproxen (for example, naproxen sodium), andcombinations thereof.

Representative muscle relaxants include, but are not limited to:carisoprodol, chlorzoxazone, cyclobenzaprine, diflunisal, metaxalone,methocarbamol, and combinations thereof.

Representative norepinephrine reuptake inhibitors include, but are notlimited to: atomoxetine, buproprion and the buproprion metabolitehydroxybuproprion, maprotiline, reboxetine (for example,(S,S)-reboxetine), viloxazine, and combinations thereof In a particularembodiment, the norepinephrine reuptake inhibitor is selected fromatomoxetine, reboxetine, and combinations thereof.

Representative opioid agonists (opioid analgesics) include, but are notlimited to: buprenorphine, butorphanol, codeine, dihydrocodeine,fentanyl, hydrocodone, hydromorphone, levallorphan, levorphanol,meperidine, methadone, morphine, nalbuphine, nalmefene, nalorphine,naloxone, naltrexone, nalorphine, oxycodone, oxymorphone, pentazocine,propoxyphene, tramadol, and combinations thereof. In certainembodiments, the opioid agonist is selected from codeine,dihydrocodeine, hydrocodone, hydromorphone, morphine, oxycodone,oxymorphone, tramadol, and combinations thereof.

Representative selective serotonin reuptake inhibitors (SSRIs) include,but are not limited to: citalopram and the citalopram metabolitedesmethylcitalopram, dapoxetine, escitalopram (e.g., escitalopramoxalate), fluoxetine and the fluoxetine desmethyl metabolitenorfluoxetine, fluvoxamine (e.g., fluvoxamine maleate), paroxetine,sertraline and the sertraline metabolite demethylsertraline, andcombinations thereof. In certain embodiments, the SSRI is selected fromcitalopram, paroxetine, sertraline, and combinations thereof.

Representative sodium channel blockers include, but are not limited to:carbamazepine, fosphenytoin, lamotrignine, lidocaine, mexiletine,oxcarbazepine, phenytoin, and combinations thereof.

Representative sympatholytics include, but are not limited to: atenolol,clonidine, doxazosin, guanethidine, guanfacine, modafinil, phentolamine,prazosin, reserpine, tolazoline (e.g., tolazoline hydrochloride),tamsulosin, and combinations thereof.

The following formulations illustrate representative pharmaceuticalcompositions of the present invention:

Exemplary Hard Gelatin Capsules for Oral Administration

A compound of the invention (50 g), spray-dried lactose (440 g) andmagnesium stearate (10 g) are thoroughly blended. The resultingcomposition is then loaded into hard gelatin capsules (500 mg ofcomposition per capsule).

Alternately, a compound of the invention (20 mg) is thoroughly blendedwith starch (89 mg), microcrystalline cellulose (89 mg) and magnesiumstearate (2 mg). The mixture is then passed through a No. 45 mesh U.S.sieve and loaded into a hard gelatin capsule (200 mg of composition percapsule).

Exemplary Gelatin Capsule Formulation for Oral Administration

A compound of the invention (100 mg) is thoroughly blended withpolyoxyethylene sorbitan monooleate (50 mg) and starch powder (250 mg).The mixture is then loaded into a gelatin capsule (400 mg of compositionper capsule).

Alternately, a compound of the invention (40 mg) is thoroughly blendedwith microcrystalline cellulose (Avicel PH 103; 259.2 mg) and magnesiumstearate (0.8 mg). The mixture is then loaded into a gelatin capsule(Size #1, White, Opaque) (300 mg of composition per capsule).

Exemplary Tablet Formulation for Oral Administration

A compound of the invention (10 mg), starch (45 mg) and microcrystallinecellulose (35 mg) are passed through a No. 20 mesh U.S. sieve and mixedthoroughly. The granules so produced are dried at 50-60° C. and passedthrough a No. 16 mesh U.S. sieve. A solution of polyvinylpyrrolidone (4mg as a 10% solution in sterile water) is mixed with sodiumcarboxymethyl starch (4.5 mg), magnesium stearate (0.5 mg), and talc (1mg), and this mixture is then passed through a No. 16 mesh U.S. sieve.The sodium carboxymethyl starch, magnesium stearate and talc are thenadded to the granules. After mixing, the mixture is compressed on atablet machine to afford a tablet weighing 100 mg.

Alternately, a compound of the invention (250 mg) is thoroughly blendedwith microcrystalline cellulose (400 mg), silicon dioxide fumed (10 mg),and stearic acid (5 mg). The mixture is then compressed to form tablets(665 mg of composition per tablet).

Alternately, a compound of the invention (400 mg) is thoroughly blendedwith cornstarch (50 mg), croscarmellose sodium (25 mg), lactose (120mg), and magnesium stearate (5 mg). The mixture is then compressed toform a single-scored tablet (600 mg of compositions per tablet).

Exemplary Suspension Formulation for Oral Administration

The following ingredients are mixed to form a suspension containing 100mg of active agent per 10 mL of suspension:

Ingredients Amount Compound of the invention 1.0 g Fumaric acid 0.5 gSodium chloride 2.0 g Methyl paraben 0.15 g Propyl paraben 0.05 gGranulated sugar 25.5 g Sorbitol (70% solution) 12.85 g Veegum ® K(magnesium aluminum silicate) 1.0 g Flavoring 0.035 mL Colorings 0.5 mgDistilled water q.s. to 100 mL

Exemplary Injectable Formulation for Administration by Injection

A compound of the invention (0.2 g) is blended with 0.4 M sodium acetatebuffer solution (2.0 mL). The pH of the resulting solution is adjustedto pH 4 using 0.5 N aqueous hydrochloric acid or 0.5 N aqueous sodiumhydroxide, as necessary, and then sufficient water for injection isadded to provide a total volume of 20 mL. The mixture is then filteredthrough a sterile filter (0.22 micron) to provide a sterile solutionsuitable for administration by injection.

Exemplary Compositions for Administration by Inhalation

A compound of the invention (0.2 mg) is micronized and then blended withlactose (25 mg). This blended mixture is then loaded into a gelatininhalation cartridge. The contents of the cartridge are administeredusing a dry powder inhaler, for example.

Alternately, a micronized compound of the invention (10 g) is dispersedin a solution prepared by dissolving lecithin (0.2 g) in demineralizedwater (200 mL). The resulting suspension is spray dried and thenmicronized to form a micronized composition comprising particles havinga mean diameter less than about 1.5 μm. The micronized composition isthen loaded into metered-dose inhaler cartridges containing pressurized1,1,1,2-tetrafluoroethane in an amount sufficient to provide about 10 μgto about 500 μg of the compound of the invention per dose whenadministered by the inhaler.

Alternately, a compound of the invention (25 mg) is dissolved in citratebuffered (pH 5) isotonic saline (125 mL). The mixture is stirred andsonicated until the compound is dissolved. The pH of the solution ischecked and adjusted, if necessary, to pH 5 by slowly adding aqueous 1Nsodium hydroxide. The solution is administered using a nebulizer devicethat provides about 10 μg to about 500 μg of the compound of theinvention per dose.

EXAMPLES

The following Preparations and Examples are provided to illustratespecific embodiments of the invention. These specific embodiments,however, are not intended to limit the scope of the invention in any wayunless specifically indicated.

The following abbreviations have the following meanings unless otherwiseindicated and any other abbreviations used herein and not defined havetheir standard meaning:

AcOH acetic acid BH₃•Me₂S borane dimethylsulphide complex BOCt-butoxycarbonyl BSA bovine serum albumin DCM dichloromethane (i.e.,methylene chloride) DIAD diisopropyl azodicarboxylate DIPEAN,N-diisopropylethylamine DMEM Dulbecco's Modified Eagle's Medium DMFN,N-dimethylformamide DMSO dimethylsulfoxide EDTAethylenediaminetetraacetic acid EtOAc ethyl acetate EtOH ethanol FBSfetal bovine serum HCTU 5-chloro-1-[bis(dimethylamino)methylene]-1H-benzotriazolium 3-oxide hexafluorophosphate hDAT human dopaminetransporter HEPES 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acidhNET human norepinephrine transporter HOBt 1-hydroxybenzotriazole,hydrate hSERT human serotonin transporter 5-HT 5-hydroxytryptamine IPAisopropanol LiHMDS lithium hexamethyl disilazide MeOH methanol NAnoradrenaline PBS phosphate buffered saline PPh₃ triphenylphosphineTEMPO 2,2,6,6-tetramethyl-1-piperidinyloxy, free radical TFAtrifluoroacetic acid THF tetrahydrofuran

Any other abbreviations used herein but not defined have their standard,generally accepted meaning. Unless noted otherwise, all materials, suchas reagents, starting materials and solvents, were purchased fromcommercial suppliers (such as Sigma-Aldrich, Fluka Riedel-de Haën, andthe like) and were used without further purification.

Assay 1 hSERT, hNET, and hDAT Binding Assays

Membrane radioligand binding assays were used to measure competitiveinhibition of labeled ligand (³H-citalopram or ³H-nisoxetine or³H-WIN35428) binding to membranes prepared from cells expressing therespective human recombinant transporter (hSERT or hNET or hDAT) inorder to determine the pK_(i) values of test compounds at thetransporters.

Membrane Preparation from Cells Expressing hSERT, hNET, or hDAT

Recombinant human embryonic kidney (HEK-293) derived cell lines stablytransfected with hSERT or hNET, respectively, were grown in DMEM mediumsupplemented with 10% dialyzed FBS (for hSERT) or FBS (for hNET), 100μg/ml penicillin, 100 μg/ml streptomycin, 2 mM L-glutamine and 250 μg/mlof the aminoglycoside antibiotic G418, in a 5% CO₂ humidified incubatorat 37° C. When cultures reached 80% confluence, the cells were washedthoroughly in PBS (without Ca²⁺ and Mg²⁺) and lifted with 5 mM EDTA inPBS. Cells were pelleted by centrifugation, resuspended in lysis buffer(10 mM Tris-HCl, pH 7.5 containing 1 mM EDTA), homogenized, pelleted bycentrifugation, then resuspended in 50 mM Tris-HCl, pH 7.5 and 10%sucrose at 4° C. Protein concentration of the membrane suspension wasdetermined using a Bio-Rad Bradford Protein Assay kit. Membranes weresnap frozen and stored at −80° C. Chinese hamster ovary membranesexpressing hDAT (CHO-DAT) were purchased from PerkinElmer and stored at−80° C.

Binding Assays

Binding assays were performed in a 96-well assay plate in a total volumeof 200 μl assay buffer (50 mM Tris-HCl, 120 mM NaCl, 5 mM KCl, pH 7.4)with 0.5, 1, and 3 μg membrane protein, for SERT, NET and DAT,respectively. Saturation binding studies, to determine radioligand K_(d)values for ³H-citalopram, ³H-nisoxetine, or ³H-WIN35428, respectivelywere conducted using 12 different radioligand concentrations rangingfrom 0.005-10 nM (³H-citalopram); 0.01-20 nM (³H-nisoxetine) and 0.2-50nM (³H-WIN35428). Displacement assays for determination of pK_(i) valuesof test compounds were conducted with 1.0 nM ³H-citalopram, 1.0 nM³H-nisoxetine or 3.0 nM ³H-WIN35428, at 11 different concentrations oftest compound ranging from 10 pM to 100 μM.

Stock solutions (10 mM in DMSO) of test compound were prepared andserial dilutions made using Dilution Buffer (50 mM Tris-HCl, 120 mMNaCl, 5 mM KCl, pH 7.4, 0.1% BSA, 400 μM ascorbic acid). Non-specificradioligand binding was determined in the presence of 1 μM duloxetine, 1μM desipramine or 10 μM GBR12909 (each in Dilution Buffer) for thehSERT, hNET or hDAT assays, respectively.

Following a 60 minute incubation at 22° C. (or a period sufficient toreach equilibrium), the membranes were harvested by rapid filtrationover a 96-well UniFilter GF/B plate, pretreated with 0.3%polyethyleneimine, and washed 6 times with 300 μl wash buffer (50 mMTris-HCl, 0.9% NaCl, pH 7.5 at 4° C.). Plates were dried overnight atroom temperature, ˜45 μl of MicroScint™-20 (Perkin Elmer) added andbound radioactivity quantitated via liquid scintillation spectroscopy.Competitive inhibition curves and saturation isotherms were analyzedusing GraphPad Prism Software package (GraphPad Software, Inc., SanDiego, Calif.). IC₅₀ values were generated from concentration responsecurves using the Sigmoidal Dose Response (variable slope) algorithm inPrism GraphPad. K_(d) and B_(max) values for the radioligand weregenerated from saturation isotherms using the Saturation Binding GlobalFit algorithm in Prism GraphPad. pK_(i) (negative decadic logarithm ofK_(i)) values for test compounds were calculated from the best-fit IC₅₀values, and the K_(d) value of the radioligand, using the Cheng-Prusoffequation (Cheng & Prusoff (1973) Biochem. Pharmacol. 22(23):3099-3108):K_(i)=IC₅₀/(1+[L]/K_(d)), where [L]=concentration radioligand.

All the aforementioned compounds were tested in this assay and found toexhibit a SERT pK_(i)≧5.0 and a NET pK_(i)≧5.0, with numerous compoundsexhibiting a SERT pK_(i)≧7.0 and/or NET pK_(i)≧7.0 and severalexhibiting a SERT pK_(i)≧8.0 and/or NET pK_(i)≧8.0.

Assay 2 hSERT, hNET, and hDAT Neurotransmitter Uptake Assays

Neurotransmitter uptake assays were used to measure competitiveinhibition of ³H-serotonin (³H-5-HT), ³H-norepinephrine (³H-NE), and³H-dopamine (³H-DA) uptake into cells expressing the respectivetransporter (hSERT, hNET or hDAT) in order to determine the pIC₅₀ valuesof test compounds at the transporters.

³H-5-HT ³H-NE, and ³H-DA Uptake Assays

HEK-293 derived cell lines stably-transfected with hSERT, hNET, or hDAT,respectively, were grown in DMEM medium supplemented with 10% dialyzedFBS (for hSERT) or FBS (for hNET and hDAT), 100 μg/ml penicillin, 100μg/ml streptomycin, 2 mM L-glutamine and 250 μg/ml of the aminoglycosideantibiotic G418 (for hSERT and hNET) or 800 ug/ml (for hDAT), in a 5%CO₂ humidified incubator at 37° C. When cultures reached 80% confluence,the cells were washed thoroughly in PBS (without Ca²⁺ and Mg²⁺) andlifted with 5 mM EDTA in PBS. Cells were harvested by centrifugation at1100 rpm for 5 minutes, washed once by resuspension in PBS, thencentrifuged. The supernatant was discarded and the cell pelletresuspended, by gentle trituration, in room temperature Krebs-Ringerbicarbonate buffer containing HEPES (10 mM), CaCl₂ (2.2 mM), ascorbicacid (200 μM) and pargyline (200 μM), pH 7.4. The final concentration ofcells in the cell suspension was 7.5×10⁴ cells/ml, 1.25×10⁵ cells/ml,and 5.0×10⁴ cells/ml for SERT, NET, and DAT cell lines, respectively.

Neurotransmitter uptake assays were performed in a 96-well assay platein a total volume of 400 μl assay buffer (Krebs-Ringer bicarbonatebuffer containing HEPES (10 mM), CaCl₂ (2.2 mM), ascorbic acid (200 μM)and pargyline (200 μM), pH 7.4) with 1.5×10⁴ and 2.5×10⁴ cells, for SERTand NET, respectively. Competition assays for determination of pIC₅₀values of test compounds were conducted with 11 differentconcentrations, ranging from 10 μM to 100 μM. Stock solutions (10 mM inDMSO) of test compound were prepared and serial dilutions prepared using50 mM Tris-HCl, 120 mM NaCl, 5 mM KCl, pH 7.4, 0.1% BSA, 400 μM ascorbicacid. Test compounds were incubated for 30 minutes at 37° C. with therespective cells, prior to addition of radiolabeled neurotransmitter,³H-5-HT (20 nM final concentration), ³H-NE (50 nM final concentration),or ³H-DA (100 nM final concentration). Non-specific neurotransmitteruptake was determined in the presence of 2.5 μM duloxetine or 2.5 μMdesipramine (each in Dilution Buffer) for the hSERT, hNET, or hDATassays, respectively.

Following a 10 minute incubation, at 37° C., with radioligand, the cellswere harvested by rapid filtration over a 96-well UniFilter GF/B plate,pretreated with 1% BSA, and washed 6 times with 650 μl wash buffer (icecold PBS). Plates were dried overnight at 37° C., 45 μl ofMicroScint™-20 (Perkin Elmer) added and incorporated radioactivityquantitated via liquid scintillation spectroscopy. Competitiveinhibition curves were analyzed using GraphPad Prism Software package(GraphPad Software, Inc., San Diego, Calif.). IC₅₀ values were generatedfrom concentration response curves using the Sigmoidal Dose Response(variable slope) algorithm in Prism GraphPad.

Assay 3 Ex Vivo SERT and NET Transporter Occupancy Studies

Ex vivo radioligand binding and neurotransmitter uptake assays were usedto determine the in vivo occupancy of SERT and NET, in selected brainregions, following in vivo administration (acute or chronic) of testcompounds. Following administration of test compound (by intravenous,intraperitoneal, oral, subcutaneous or other route) at the appropriatedose (0.0001 to 100 mg/kg), rats (≧n=4 per group) were euthanized atspecific time points (10 minutes to 48 hours) by decapitation and thebrain dissected on ice. Relevant brain regions were dissected, frozenand stored at −80° C. until use.

Ex Vivo SERT and NET Radioligand Binding Assays

For ex vivo radioligand binding assays, the initial rates of associationof SERT (³H-citalopram), and NET-(³H-nisoxetine) selective radioligandswith rat brain crude homogenates, prepared from vehicle and testcompound-treated animals, were monitored (see Hess et al. (2004) J.Pharmacol. Exp. Ther. 310(2):488-497). Crude brain tissue homogenateswere prepared by homogenizing frozen tissue pieces in 0.15 ml (per mgwet weight) of 50 mM Tris-HCl, 120 mM NaCl, 5 mM KCl, pH 7.4 buffer.Radioligand association assays were performed in a 96-well assay platein a total volume of 200 μl assay buffer (50 mM Tris-HCl, 120 mM NaCl, 5mM KCl, 0.025% BSA, pH 7.4) with 650 μg wet weight tissue (equivalent to25 μg protein). Homogenates were incubated for up to 5 minutes with³H-citalopram (3 nM) and ³H-nisoxetine (5 nM), respectively, prior totermination of the assay by rapid filtration over a 96-well UniFilterGF/B plate, pretreated with 0.3% polyethyleneimine. Filters then werewashed 6 times with 300 μl wash buffer (50 mM Tris-HCl, 0.9% NaCl, pH7.4 at 4° C.). Non-specific radioligand binding was determined in thepresence of 1 μM duloxetine, or 1 μM despiramine, for ³H-citalopram or³H-nisoxetine, respectively. The plates were dried overnight at roomtemperature, ˜45 μl of MicroScint™-20 (Perkin Elmer) added and boundradioactivity quantitated via liquid scintillation spectroscopy. Theinitial rates of association of ³H-citalopram and ³H-nisoxetine weredetermined by linear regression using GraphPad Prism Software package(GraphPad Software, Inc., San Diego, Calif.). The average rate ofradioligand association to brain tissue homogenates from vehicle-treatedanimals was determined. The % occupancy of test compounds then wasdetermined using the following equation:% occupancy=100×(1−(initial rate association for test compound-treatedtissue/mean rate association for vehicle-treated tissue))ED₅₀ values were determined by plotting the log 10 of the dose of thetest compound against the % occupancy. ED₅₀ values were generated fromconcentration response curves using the Sigmoidal Dose Response(variable slope) algorithm in GraphPad Prism.

Ex Vivo SERT and NET Uptake Assays

Ex vivo neurotransmitter uptake assays, in which the uptake of ³H-5-HTor ³H-NE into rat brain crude homogenates, prepared from vehicle andtest compound-treated animals, were used to measure in vivo SERT and NETtransporter occupancy (see Wong et al. (1993) Neuropsychopharmacology8(1):23-33). Crude brain tissue homogenates were prepared byhomogenizing frozen tissue pieces in 0.5 ml (per mg wet weight) of 10 mMHEPES buffer pH 7.4, containing 0.32 M sucrose, 200 μM ascorbic acid and200 μM pargyline, at 22° C. Neurotransmitter uptake assays wereperformed in a 96-well Axygen plate in a total volume of 350 μl assaybuffer (Krebs-Ringer bicarbonate buffer with 10 mM HEPES, 2.2 mM CaCl₂,200 μM ascorbic acid and 200 μM pargyline, pH 7.4) with 50 μg protein.Homogenates were incubated for 5 minutes at 37° C. with ³H-5-HT (20 nM)and ³H-NE (50 nM), respectively, prior to termination of the assay byrapid filtration over a 96-well UniFilter GF/B plate, pretreated with 1%BSA. Plates were washed 6 times with 650 μl wash buffer (ice cold PBS)and dried overnight at 37° C., prior to addition of ˜45 μl ofMicroScint™-20 (Perkin Elmer) added. Incorporated radioactivity wasquantitated via liquid scintillation spectroscopy. Non-specificneurotransmitter uptake was determined in parallel assays in whichtissue homogenates were incubated with ³H-5-HT (20 nM) or ³H-NE (50 nM)for 5 minutes at 4° C.

Assay 4 Other Assays

Other assays that were used to evaluate the pharmacological propertiesof test compounds include, but are not limited to, cold ligand bindingkinetics assays (Motulsky and Mahan (1984) Molecular Pharmacol. 25(1):1-9) with membranes prepared from cells expressing hSERT or hNET;conventional membrane radioligand binding assays using radiolabeled, forexample, tritiated, test compound; radioligand binding assays usingnative tissue from, for example rodent or human brain; neurotransmitteruptake assays using human or rodent platelets; neurotransmitter uptakeassays using crude, or pure, synaptosome preparations from rodent brain.

Assay 5 Formalin Paw Test

Compounds are assessed for their ability to inhibit the behavioralresponse evoked by a 50 μl injection of formalin (5%). A metal band isaffixed to the left hind paw of male Sprague-Dawley rats (200-250 g) andeach rat is conditioned to the band for 60 minutes within a plasticcylinder (15 cm diameter). Compounds are prepared in pharmaceuticallyacceptable vehicles and administered systemically (i.p., p.o.) atpre-designated times before formalin challenge. Spontaneous nociceptivebehaviors consisting of flinching of the injected (banded) hind paw arecounted continuously for 60 minutes using an automated nociceptionanalyzer (UCSD Anesthesiology Research, San Diego, Calif.).Antinociceptive properties of test articles are determined by comparingthe number of flinches in the vehicle and compound-treated rats (Yaksh TL, et al., “An automated flinch detecting system for use in the formalinnociceptive bioassay” (2001) J. Appl. Physiol. 90(6):2386-2402).

Assay 6 Spinal Nerve Ligation Model

Compounds are assessed for their ability to reverse tactile allodynia(increased sensitivity to an innocuous mechanical stimulus) induced bynerve injury. Male Sprague-Dawley rats are surgically prepared asdescribed in Kim and Chung “An experimental model for peripheralneuropathy produced by segmental spinal nerve ligation in the rat”(1992) Pain 50(3):355-363. Mechanical sensitivity is determined as the50% withdrawal response to innocuous mechanical stimuli (Chaplan et al.,“Quantitative assessment of tactile allodynia in the rat paw” (1994) J.Neurosci. Methods 53(1):55-63) before and after nerve injury. One tofour weeks post-surgery, compounds are prepared in pharmaceuticallyacceptable vehicles and administered systemically (i.p., p.o.). Thedegree of nerve injury-induced mechanical sensitivity before and aftertreatment serves as an index of the compounds' antinociceptiveproperties.

Powder X-Ray Diffraction

Powder X-ray diffraction patterns were obtained with a Rigaku MiniflexPXRD diffractometer using Cu Kα (30.0 kV, 15.0 mA) radiation. Analyseswere performed with the goniometer running in continuous-scan mode of 2°(2θ) per min with a step size of 0.03° over a range of 2 to 40° intwo-theta angle. Samples were prepared on quartz specimen holders as athin layer of powdered material. The instrument was calibrated with asilicon metal standard, within ±0.02° two-theta angle.

Thermal Analysis

Differential scanning calorimetry (DSC) was performed using a TAInstruments Model Q-100 module with a Thermal Analyst controller. Datawere collected and analyzed using TA Instruments Thermal Solutionssoftware. A 1.64 mg sample of the crystalline form of Example 2 wasaccurately weighed into a covered aluminum pan. After a 5 minuteisothermal equilibration period at 22° C., the sample was heated using alinear heating ramp of 10° C./min from 22° C. to 250° C.

Thermogravimetric analysis (TGA) was performed using a TA InstrumentsModel Q-50 module equipped with high resolution capability. Data werecollected and analyzed using TA Instruments Thermal Solutions software.A sample weighing about 2 mg was placed onto a platinum pan and scannedwith a high resolution-heating rate from ambient temperature to 300° C.The balance and furnace chambers were purged with nitrogen flows duringuse.

Preparation 1 3-Benzoyl-2-oxopyrrolidine-1-carboxylic Acid t-Butyl Ester

To a stirred solution of 1-(t-butoxycarbonyl)-2-pyrrolidinone (11.9 g,64.3 mmol) in dry THF (190 mL) at −78° C. was added a solution of LiHMDS(1.0M in toluene, 135 mL, 135 mmol). After stirring at −78° C. for 2hours, benzoyl chloride (7.5 mL, 64.3 mmol) was added dropwise over 5minutes while keeping the temperature below −50° C. The mixture wasstirred at −78° C. for 4 hours, and the reaction was then quenched witha saturated aqueous NH₄Cl solution (200 mL). The mixture was dilutedwith EtOAc (300 mL) and the organic layer was washed with saturatedNaHCO₃ (200 mL×2) and saturated aqueous NaCl (200 mL). The organic layerwas dried over MgSO₄, filtered and concentrated, and the crude productwas purified by flash column chromatography (20-60% EtOAc in hexanes) toafford the title compound (14.5 g) as a yellow oil.

MS m/z: [M+H]⁺ calcd for C₁₆H₁₉NO₄, 290.13. ¹H-NMR (400 MHz, CD₃OD):δ(ppm)=8.09-8.07 (m, 2H), 7.67-7.63 (m, 1H), 7.56-7.52 (m, 2H), 4.86(obscure, 1H, overlap with water solvent), 3.89-3.78 (m, 2H), 2.47-2.42(m, 1H), 2.34-2.29 (m, 1H), 1.55 (s, 9H).

Preparation 2 3-(Hydroxyphenylmethyl)pyrrolidine-1-carboxylic Acidt-Butyl Ester

Under nitrogen, BH₃.Me₂S (13.1 mL, 138 mmol) was added dropwise over 10minutes to a mixture of 3-benzoyl-2-oxopyrrolidine-1-carboxylic acidt-butyl ester (8.0 g, 28 mmol) dissolved in dry THF (90 mL). The mixturewas stirred at room temperature for 1 hour, heated at 65° C. for 1 hourand cooled to room temperature. The mixture was slowly quenched withpre-cooled MeOH (25 mL). After completion of the addition, the mixturewas diluted with EtOAc (75 mL) and washed with saturated aqueous NaHCO₃solution (2×50 mL). The organic layer was dried over MgSO₄, filtered andconcentrated in vacuo to obtain a crude mixture containing a 3:1RS/SR:SS/RR mixture of stereoisomers. The crude product was purified byreverse phase preparative HPLC to obtain the RS/SR mixture ofenantiomers (white solid, 2.4 g) and the SS/RR mixture of enantiomers(clear oil, 1.0 g) of the title compound.

RS/SR mixture of enantiomers: MS m/z: [M+H]⁺ calcd for C₁₆H₂₃NO₃,278.36. Found 278.3. ¹H-NMR (400 MHz, DMSO-d₆): δ(ppm)=7.32 (m, 4H),7.27-7.22 (m, 1H), 4.40 (d, J=7.2, 1H), 3.32 (m, 1H), 3.15-3.10 (m, 1H),3.00-2.88 (m, 2H), 2.45-2.35 (m, 1H), 1.88-1.75 (m, 2H), 1.35 (s, 9H).

SS/RR mixture of enantiomers: MS m/z: [M+H]⁺ calcd for C₁₆H₂₃NO₃,278.36. Found 278.3. ¹H-NMR (400 MHz, DMSO-d₆): δ(ppm)=7.33 (m, 4H),7.25-7.23 (m, 1H), 4.36 (t, J=6.8, 1H), 3.36-3.27 (m, 2H), 3.17-3.09 (m,2H), 2.45-2.33 (m, 2H), 1.55-1.40 (m, 1H), 1.38 (s, 9H).

Preparation 3 3-(Phenyl-o-tolyloxymethyl)pyrrolidine-1-carboxylic Acidt-Butyl Ester (3a; R²═—CH₃),3-(Phenoxyphenylmethyl)pyrrolidine-1-carboxylic Acid t-Butyl Ester (3b;R²═H), and 3-[(2-Methoxyphenoxy)phenylmethyl]pyrrolidine-1-carboxylicAcid t-Butyl Ester (3c; R²═—OCH₃)

3-(Phenyl-o-tolyloxymethyl)pyrrolidine-1-carboxylic acid t-butyl ester(3a): Under air, the RS/SR mixture of enantiomers of3-(hydroxyphenylmethyl)pyrrolidine-1-carboxylic acid t-butyl ester (156mg, 0.56 mmol), 2-iodotoluene (144 μl, 1.1 mmol), CuI (22 mg, 112 μmol),1,10-phenanthroline (41 mg, 224 μmol) and Cs₂CO₃ (365 mg, 1.1 mmol) indry toluene (0.5 mL) were combined in a sealed tube and heated at 120°C. for 48 hours. The mixture was cooled to room temperature and dilutedwith DCM, passed through a pad of Celite. The filtrate was purified byflash chromatography on silica gel (hexane/EtOAc:10/1) to yield titlecompound 3a (149 mg) as a yellow oil. ¹H-NMR (300 MHz, DMSO-d₆): δ(ppm)=7.41-7.32 (m, 4H), 7.31-7.24 (m, 1H), 7.10 (m, 1H), 6.95 (m, 1H),6.71 (m, 2H), 5.29 (d, J=7.2, 1H), 3.44-3.35 (m, 1H), 3.26-3.18 (m, 1H),3.16-3.04 (m, 2H), 2.73-2.68 (m, 1H), 2.24 (s, 3H), 2.10-1.96 (m, 1H),1.94-1.81 (m, 1H), 1.37 (m, 9H).

Title compound 3b was synthesized in a similar manner using iodobenzeneas the aryl halide (47% yield).

Under air, the RS/SR mixture of enantiomers of3-(hydroxyphenylmethyl)-pyrrolidine-1-carboxylic acid t-butyl ester (382mg, 1.4 mmol), was dissolved in dry toluene (2.2 mL). To this was added2-iodoanisole (360 μl, 2.8 mmol), CuI (80 mg, 0.4 mmol),1,10-phenanthroline (100 mg, 0.8 mmol) and Cs₂CO₃ (897 mg, 2.8 mmol).Air was bubbled through the reaction mixture, sealed tightly, and heatedat 105° C. over 48 hours. The mixture was cooled to room temperature,rinsed with DCM, filtered, and concentrated to afford title compound 3cas an oily residue, which was used without further purification.

Compounds 3a, 3b, and 3c were obtained as a RS/SR mixtures ofenantiomer.

Example 1 3-(Phenyl-o-tolyloxymethyl)pyrrolidine

3-(Phenyl-o-tolyloxymethyl)pyrrolidine-1-carboxylic acid t-butyl ester(149 mg, 405 μmol) was dissolved in a solution of HCl in EtOH (1.25M, 3mL) and stirred at room temperature for 3 hours, and then evaporated todryness. The residue was purified by flash chromatography on silica gel(CH₂Cl₂/MeOH:9/1) to afford the RS/SR mixture of enantiomers of thehydrochloride salt of the title compound as a yellow foam (112 mg, 98%purity).

MS m/z: [M+H]⁺ calcd for C₁₈H₂₁NO, 268.16. Found 267.36. Found forC₁₈H₂₁NO.HCl, 303.84. ¹H-NMR (300 MHz, DMSO-d₆): MS-APCI: 268 ([M+H]⁺,100). Analytical HPLC (gradient: 5 min, 5%→100% acetonitrile): R^(t) inmin (integration): 5.05 (98%). δ (ppm)=9.18 (bs, 2H), 7.44-7.32 (m, 4H),7.30-7.26 (m, 1H), 7.10 (m, 1H), 6.99-6.93 (m, 1H), 6.77-6.66 (m, 2H),5.45 (d, J=6.8, 1H), 3.41-3.35 (m, 1H), 3.26-3.10 (m, 2H), 3.01-2.92 (m,1H), 2.82-2.77 (m, 1H), 2.27 (s, 3H), 2.12-1.97 (m, 2H).

Example 2 3-[(2-Methoxyphenoxy)phenylmethyl]pyrrolidine

3-[(2-Methoxyphenoxy)phenylmethyl]pyrrolidine-1-carboxylic acid t-butylester was dissolved in a solution of HCl in EtOH (1.25M, 8 mL) andstirred at room temperature for 18 hours, and then evaporated todryness. The residue was purified by reverse phase preparative HPLC toafford the TFA salt of the RS/SR mixture of enantiomers of the titlecompound as a TFA salt (90 mg, 95% purity). MS m/z: [M+H]⁺ calcd forC₁₈H₂₁NO₂, 284.16. Found 284.4. ¹H NMR (CD₃OD, 400 MHz) δ (ppm):7.40-7.35 (m, 4H), 7.32-7.28 (m, 1H), 7.00-6.98 (m, 1H), 6.92-6.88 (m,1H), 6.71-6.65 (m, 2H), 5.32 (d, J=5.2, 1H), 3.90 (s, 3H), 3.62-3.55 (m,1H), 3.36-3.30 (obscure, 3H, overlap with solvent), 2.97-2.92 (m, 1H),2.28-2.21 (m, 1H), 2.13-2.07 (m, 1H).

Example 3 3-[(3,5-Dichlorophenoxy)phenylmethyl]pyrrolidine

Using a method similar to that of Example 2, and, in Preparation 3,substituting 2-iodoanisole with 1,3-dichloro-5-iodobenzene, the TFA saltof the RS/SR mixture of enantiomers of the title compound was prepared(437 mg, 99% purity). MS m/z: [M+H]⁺ calcd for C₁₇H₁₇Cl₂NO, 322.07.Found, 322.2. ¹H NMR (CD₃OD, 400 MHz) δ (ppm): 7.41-7.39 (m, 4H),7.35-7.33 (m, 1H), 6.96 (s, 1H), 6.88 (s, 2H), 5.40 (d, J=6.0, 1H),3.48-3.43 (m, 1H), 3.31-3.25 (obscure, 2H, overlap with solvent),3.17-3.14 (m, 1H), 2.98-2.92 (m, 1H), 2.17-2.11 (m, 2H).

Example 4 3-(Phenyl-o-tolyloxymethyl)pyrrolidine (4-1; R²═—CH₃) and3-[(2-Methoxyphenoxy)phenylmethyl]pyrrolidine (4-2; R²═—OCH₃)

The title compounds were prepared as TFA salts using a method similar tothat of Example 2, and, in Preparation 3, substituting the RS/SR mixtureof enantiomers with the SS/RR mixture of enantiomers of3-(hydroxyphenylmethyl)pyrrolidine-1-carboxylic acid t-butyl ester (47.5mg, 0.2 mmol), and substituting 2-iodoanisole with the appropriate aryliodide.

The SS/RR mixture of enantiomers of title compound 4-1 (13.8 mg): MSm/z: [M+H] calcd for C₁₈H₂₁NO, 268.16. Found 268.2.

The SS/RR mixture of enantiomers of title compound 4-2 (11.2 mg): MSm/z: [M+H]⁻ calcd for C₁₈H₂₁NO₂, 284.16. Found, 284.4. ¹H NMR (CD₃OD,400 MHz) δ (ppm): 7.41-7.30 (m, 5H), 6.98-6.96 (m, 1H), 6.91-6.86 (m,1H), 6.70-6.63 (m, 2H), 5.20 (d, J=6.8, 1H), 3.89 (s, 3H), 3.53-3.46 (m,3H), 3.31-3.30 (obscure, 1H, overlap with solvent), 2.98-2.96 (m, 1H),2.02-1.95 (m, 2H).

Example 5 3-[(2-Ethoxyphenoxy)phenylmethyl]pyrrolidine

A mixture of the SS/RR mixture of enantiomers of3-(hydroxyphenylmethyl)-pyrrolidine-1-carboxylic acid t-butyl ester (30mg, 0.11 mmol), 2-ethoxyphenol (16 μL, 0.13 mmol), and PPh₃ (29.8 mg,114 μmol) in THF (0.09 mL) was sonicated for several minutes. Whilesonicating, DIAD (22.4 μL, 114 μmol) was added dropwise to the reactionmixture over a couple minutes and sonicated further for 15 minutes. Thereaction was concentrated to yield the BOC-protected form of the titlecompound as an oily residue, which was used without furtherpurification.

The BOC-protected compound was dissolved in a solution of HCl in EtOH(1.25M, 0.7 mL) and stirred at room temperature for 18 hours, and thenevaporated to dryness. The residue was purified by reverse phasepreparative HPLC to afford the TFA salt of the RS/SR mixture ofenantiomers of the title compound (23.2 mg, 97% purity). MS m/z: [M+H]⁻calcd for C₁₉H₂₃NO₂, 298.17. Found, 298.6.

Example 6 Separation of the RS/SR Mixture of Enantiomers of3-[(2-methoxyphenoxy)phenylmethyl]pyrrolidine into the RS (6-1) and SR(6-2) Enantiomers

The RS/SR mixture of enantiomers of3-[(2-methoxyphenoxy)phenylmethyl]-pyrrolidine was prepared as describedin Example 2 and subsequently made into a 40 mg/mL solution in MeOH. TheRS and SR enantiomers were separated by a chiral column. The column wasa Chiralpak AD-H-SFC (10 mm×250 mm, 5 micron particle size) containingamylase tris-(3,5-dimethylphenylcarbamate). Solvent A was CO₂ andSolvent B was MeOH with 0.1% triethylamine. 8% Solvent B was run at 10mL/min with 200 Barr back pressure. A 20 mL injection of the 40 mg/mLsolution was used.

RS enantiomer compound 6-1: MS m/z: [M+H]⁺ calcd for C₁₈H₂₁NO₂, 284.16.Found 284.4; SFC: 10.3 min.

SR enantiomer compound 6-2: MS m/z: [M+H]⁺ calcd for C₁₈H₂₁NO₂, 284.16.Found 284.4. SFC: 12.4 min.

Preparation 4 (S)-3-Formylpyrrolidine-1-carboxylic Acid t-Butyl Ester

To a solution of (S)-3-hydroxymethylpyrrolidine-1-carboxylic acidt-butyl ester (7.4 g, 37 mmol) in DCM (74 mL, 1.2 mol) was added TEMPO(100 mg, 0.7 mmol) and potassium bromide (200 mg, 2 mmol). This mixturewas cooled to 0° C. and vigorously stirred as a pre-chilled (at 0° C.)1:1 mixture of 0.7 M of NaOCl in water (78 mL, 55 mmol) and a saturated,aqueous NaHCO₃ solution (75 mL) was added dropwise over a period of 10minutes. The resultant mixture was extracted with DCM (3×100 mL). Thecombined organic layers were washed with water (2×100 mL), thensaturated aqueous NaCl (1×100 mL). The organic layer was dried overanhydrous Na₂SO₄, filtered and concentrated in vacuo to yield the titlecompound, which was used without further purification (5.8 g).

Preparation 5 (S)-3-((R)-Hydroxyphenylmethyl)pyrrolidine-1-carboxylicAcid t-Butyl Ester and(S)-3-((S)-Hydroxyphenylmethyl)pyrrolidine-1-carboxylic Acid t-ButylEster

(S)-3-Formylpyrrolidine-1-carboxylic acid t-butyl ester (5.8 g, 29.1mmol) in THF (140 mL, 1.7 mol) was placed in a flask under nitrogen, andthe solution was cooled to −78° C. 1.0 M of phenylmagnesium bromide inTHF (43.7 mL, 43.7 mmol) was added dropwise over 20 minutes. Thesolution was allowed to warm to room temperature overnight, then 250 mLsaturated NH₄Cl was added dropwise to quench the reaction. The resultingmixture was extracted with EtOAc (3×150 mL), and the combined organiclayers were washed with saturated aqueous NaHCO₃ (1×100 mL) andsaturated aqueous NaCl (1×100 mL), then dried over anhydrous Na₂SO₄,filtered, and concentrated in vacuo. The product was combined with aseparate lot of material, purified and separated by preparative HPLC toyield 3.2 g of the (S,R) and 3.1 g of the (S,S) title compounds as TFAsalts. The absolute stereochemistry of the products was determined bycomparison with a crystal structure of previously synthesized(S)-3-((S)-hydroxyphenylmethyl)pyrrolidine-1-carboxylic acid t-butylester.

Example 7 (S) -3-[(R)-(2,4-Difluorophenoxy)phenylmethyl]pyrrolidine

(S)-3-((R)-Hydroxyphenylmethyl)pyrrolidine-1-carboxylic acid t-butylester (250 mg, 0.9 mmol), copper(I) iodide (51 mg, 270 μmol),1,10-phenanthroline (97 mg, 540 μmol) and 2,4-difluoro-1-iodobenzene(216 μL, 1.8 mmol) were combined. Toluene (1.4 mL, 14 mmol) was added,followed by the addition of cesium carbonate (587 mg, 1.8 mmol). Air wasbubbled through the mixture, the vessel was sealed, and the mixture washeated at 105° C. for 48 hours. The mixture was filtered, rinsed withDCM, and concentrated. The remaining material was treated with 1.25 M ofHCl in EtOH (5.8 mL, 7.2 mmol) and stirred overnight. The mixture wasconcentrated, redissolved in a 1:1 AcOH:H₂O solution and purified bypreparative HPLC to yield 76 mg (97% purity) of the title compound asthe TFA salt. MS m/z: [M+H]⁺ calcd for C₁₇H₁₇F₂NO, 290.13. Found 290.2.

Example 8(S)-3-[(R)-(2-Chloro-3,5-difluorophenoxy)phenylmethyl]pyrrolidine (8-1)and (R)-3-[(S)-(2-Chloro-3,5-difluorophenoxy)phenylmethyl]pyrrolidine(8-2)

(S)-3-((S)-Hydroxyphenylmethyl)pyrrolidine-1-carboxylic acid t-butylester (250 mg, 0.9 mmol), PPh₃ (248 mg, 946 μmol) and2-chloro-3,5-difluorophenol (222 mg, 1.4 mmol) were combined in THF (512μL, 6.3 mmol). The mixture was sonicated for several minutes. Whilesonicating, DIAD (186 μL, 946 μmol) was added dropwise over a fewminutes, then the mixture was sonicated for an additional 15 minutes.The mixture was concentrated, redissolved in 1.25M of HCl in EtOH (5 mL,6 mmol) and stirred overnight. The mixture was concentrated, redissolvedin 6 mL 1:1 AcOH:H₂O solution, and purified by preparative HPLC to yieldcompound (8-1) as the TFA salt. MS m/z: [M+H]⁻ calcd for C₁₇H₁₆ClF₂NO,324.09. Found 324.4.

The TFA salt of compound (8-2) was prepared in a similar manner, andusing (R)-3-((R)-hydroxyphenylmethyl)pyrrolidine-1-carboxylic acidt-butyl ester (250 mg, 0.9 mmol) as the starting material. MS m/z:[M+H]⁺ calcd for C₁₇H₁₆ClF₂NO, 324.09. Found 324.6.

Example 9

(S)-3-((R)-Hydroxyphenylmethyl)pyrrolidine-1-carboxylic acid t-butylester (50 mg, 0.2 mmol) was dissolved in DMF (660 μL, 8.5 mmol). Washedand dried sodium hydride (5.19 mg, 216 μmol) was slowly added. Themixture was stirred at room temperature for 15 minutes. The material wasdecanted and added directly into each of 5 vials containing the desiredaryl fluoride. The mixtures were stirred at 70° C. for 3 hours. Thecrude mixtures were concentrated, dissolved in 1.20 M of HCl in EtOH(880 μL, 1.0 mmol), and stirred overnight. The mixtures wereconcentrated and purified by preparative HPLC to yield the followingcompounds as their TFA salts:

Ex. Ar—F (amt) Product 9-1 1-fluoro-2-methanesulfonyl-(S)-3-[(R)-(2-methanesulfonylphenoxy)- benzene (120 mg)phenylmethyl]pyrrolidine. MS m/z: [M + H]⁺ calcd for C₁₈H₂₁NO₃S, 332.12;found 332.0. (61.1 mg, 99% purity) 9-2 1-fluoro-3-nitrobenzene (100 mg)(S)-3-[(R)-(3-nitrophenoxy)phenylmethyl] pyrrolidine MS m/z: [M + H]⁺calcd for C₁₇H₁₈N₂O₃, 299.13; found 299.2. (45.4 mg, 99% purity) 9-31-(2-fluorophenyl)ethanone 1-[2-((R)-phenyl-(S)-pyrrolidin-3-yl- (100mg) methoxy)phenyl]ethanone MS m/z: [M + H]⁺ calcd for C₁₉H₂₁NO₂,296.16; found 296.2. (9.3 mg, 97% purity) 9-42-chloro-1,3-difluorobenzene (S)-3-[(R)-(2-chloro-3-fluorophenoxy) (110mg) phenylmethyl]pyrrolidine MS m/z: [M + H]⁺ calcd for C₁₇H₁₇ClFNO,306.10; found 306.0. (41.7 mg, 98% purity) 9-5 2-fluorobenzoic acidmethyl 2-((R)-phenyl-(S)-pyrrolidin-3-yl-methoxy) ester (110 mg) benzoicacid methyl ester MS m/z: [M + H]⁺ calcd for C₁₉H₂₁NO₃, 312.15; found312.2. (37.8 mg, 90% purity)

Example 10 RS/SR Mixture of Enantiomers of3-[(2,6-Dichloro-3,5-difluorophenoxy)phenylmethyl]pyrrolidine (10-1) andRS/SR Mixture of Enantiomers of3-[phenyl-(2,3,5,6-tetrachlorophenoxy)methyl]pyrrolidine (10-2)

The SS/RR mixture of enantiomers of3-(hydroxyphenylmethyl)pyrrolidine-1-carboxylic acid t-butyl ester (250mg, 0.90 mmol), 2,6-dichloro-3,5-difluorophenol (359 mg, 1.8 mmol), andPPh₃ (248 mg, 946 μmol) in THF (0.7 mL, 9 mmol) was sonicated forseveral minutes. While sonicating, DIAD (186 μL, 946 μmol) was addeddropwise to the reaction mixture over a couple minutes and thensonicated further for 15 minutes. The reaction was concentrated,redissolved in 1.25 M HCl in EtOH (6 mL), and stirred overnight. Thereaction mixture was concentrated and redissolved in 1:1 AcOH:H₂Osolution, and purified by preparative HPLC to afford the TFA salt of theRS/SR mixture of enantiomers of compound (10-1) (86 mg, 97% purity). MSm/z: [M+H]⁺ calcd for C₁₇H₁₅Cl₂F₂NO, 358.05. Found 358.0.

The TFA salt of the RS/SR mixture of enantiomers of compound (10-2) wasprepared in a similar manner using 2,3,5,6-tetrachlorophenol (9.5 g,100% purity). MS m/z: [M+H]⁺ calcd for C₁₇H₁₅Cl₄NO, 389.99. Found 390.0.

Example 11(S)-3-[(R)-(2,6-dichloro-3,5-difluorophenoxy)phenylmethyl]pyrrolidine

A mixture of (S)-3-((S)-hydroxyphenylmethyl)pyrrolidine-1-carboxylicacid t-butyl ester (600 mg, 2 mmol), 2,6-dichloro-3,5-difluorophenol(516 mg, 2.6 mmol), and PPh₃ (596 mg, 2.3 mmol) in THF (1.2 mL, 15.1mmol) was sonicated for several minutes. While sonicating, DIAD (447 μL,2.3 mmol) was added dropwise to the mixture over a couple minutes andsonicated further for 15 minutes. The mixture was concentrated to yieldthe BOC-protected form of the title compound as a yellow oil, which wasused without further purification.

The BOC-protected compound was dissolved in 1.25 M HCl in EtOH (10 mL,20 mmol) and stirred at room temperature for 18 hours, and thenevaporated to dryness. The residue was purified by reverse phasepreparative HPLC to afford the title compound as a TFA salt (449 mg, 96%purity). MS m/z: [M+H]⁺ calcd for C₁₇H₁₅Cl₂F₂NO, 358.05. Found, 358.2.¹H NMR (CD₃OD, 400 MHz) δ (ppm): 7.45-7.42 (m, 2H), 7.36-7.33 (m, 3H),7.09-7.04 (m, 1H), 5.75 (d, J=8.8, 1H), 3.51-3.48 (m, 1H), 3.41-3.36 (m,1H), 3.21-3.16 (m, 2H), 2.93-2.87 (m, 1H), 2.55-2.52 (m, 1H), 2.41-2.36(m, 1H).

Monohydrochloride Crystalline Salt

A mixture of (S)-3-((S)-hydroxyphenylmethyl)pyrrolidine-1-carboxylicacid t-butyl ester (7.9 g, 28.5 mmol), 2,6-dichloro-3,5-difluorophenol(6.8 g, 34.2 mmol) and PPh₃ (7.8 g, 29.9 mmol) in THF (16.2 mL, 199mmol) was sonicated for several minutes. While sonicating, DIAD (5.9 mL,29.9 mmol) was slowly added dropwise to the mixture over several minutesand sonicated further for 15 minutes. A second mixture of(S)-3-((S)-hydroxyphenylmethyl)pyrrolidine-1-carboxylic acid t-butylester (2.0 g, 7.21 mmol), 2,6-dichloro-3,5-difluorophenol (1.7 g, 8.7mmol) and PPh₃ (2.0 g, 7.6 mmol) in THF (4.1 mL, 50.5 mmol) wassonicated for several minutes. While sonicating, DIAD (1.5 mL, 7.6 mmol)was slowly added dropwise to the reaction mixture over several minutesand sonicated further for 15 minutes. The mixtures were combined andconcentrated. The crude material was triturated in hexanes for 12 hours.The PPh₃ oxide precipitate was filtered off, and the organic layer wasconcentrated to yield 20 g of a yellow oil. The crude mixture wasdiluted in EtOAc (300 mL) and washed with 1N NaOH (2×200 mL) to removeexcess phenol. The organic layer was dried with anhydrous MgSO₄,filtered, and concentrated to yield 18.7 g of(S)-3-[(R)-(2,6-dichloro-3,5-difluorophenoxy)phenyl-methyl]pyrrolidine-1-carboxylicacid t-butyl ester as a sticky yellow oil which was used in the nextstep without further purification.

The oily residue from the previous step was dissolved in 1.25M HCl inEtOH (200 mL, 0.2 mol) and stirred at room temperature for 18 hours, andthen evaporated to dryness. EtOAc (200 mL) was added, and the resultingslurry was stirred for 2 hours. The solid material was rinsed with EtOAcand ether, and dried by lyophilization to yield 7.9 of an impure HClsalt. The material was dissolved in a 1:1 isopropyl alcohol:DCM mixturewith minimal MeOH. The crude product was purified by flash columnchromatography (40-70% IPA in DCM, 330 g column. The isolated materialwas diluted in EtOAc (200 mL) and freebased with saturated NaHCO₃ (2×200mL), washed with saturated aqueous NaCl, dried with MgSO₄, filtered, andconcentrated to yield 4.6 g of a pale white solid. The freebasedmaterial was then retreated with 1.0 eq of 1.25M HCl in EtOH (10.3 mL)and heated in order to dissolve all solids. The solution was thenconcentrated to yield(S)-3-[(R)-(2,6-dichloro-3,5-difluorophenoxy)phenylmethyl]pyrrolidine asa monohydrochloride crystalline salt (4.2 g, 30% yield, 98.4% purity).MS m/z: [M+H]⁺ calcd for C₁₇H₁₅Cl₂F₂NO, 358.05. Found, 358.2. ¹H NMR(DMSO-d₆, 400 MHz) δ (ppm): 7.56-7.50 (m, 1H), 7.41-7.32 (m, 5H), 5.70(d, J=9.2 Hz, 1H), 3.38-3.29 (obscure, 1H, overlap with solvent),3.27-3.19 (m, 2H), 3.01-2.96 (m, 1H), 2.71-2.66 (m, 1H), 2.37-2.28 (m,1H), 2.23-2.18 (m, 1H).

Powder X-Ray Diffraction

The PXRD pattern for the monohydrochloride salt showed the material tobe crystalline. A representative PXRD pattern for a sample of thiscrystalline salt is shown in FIG. 1, and the peak positions are listedin the table below:

2-Theta Angle d-spacing Intensity Relative (Degree) (Å) (Counts)intensity, % 5.84 15.126 882 5.7 12.53 7.058 5073 33.1 15.23 5.812 15009.8 17.00 5.213 4617 30.1 19.39 4.573 2846 18.6 22.79 3.899 15332 100.024.50 3.630 6810 44.4 27.35 3.258 6102 39.8 31.64 2.826 4582 29.9 34.042.632 2991 19.5Thus, this crystalline salt can be characterized by a PXRD patternhaving two or more diffraction peaks at 2θ values selected from 5.8±0.2,12.5±0.2, 15.2±0.2, 17.0±0.2, 19.4±0.2, 22.8±0.2, 24.5±0.2, 27.4±0.2,31.6±0.2, and 34.0±0.2. In particular, crystalline salt can becharacterized by a powder x-ray diffraction pattern comprisingdiffraction peaks at 2θ values of 12.5±0.2, 22.8±0.2, 24.5±0.2, and27.4±0.2.

Thermal Analysis

A representative DSC trace for a sample of this crystallinemonohydrochloric acid salt (FIG. 2) showed that the crystalline salt hasgood thermal stability with the melting peak at about 194.1° C. and nothermal decomposition below 190.7° C.

A representative TGA trace for a sample of this crystallinemonohydrochloric acid salt showed a loss of solvents and/or water(<0.5%) at temperatures below 150° C., as seen in FIG. 3. This TGA traceindicate that the crystalline salt lost a small amount of weight fromroom temperature to moderately elevated temperatures, which isconsistent with the loss of residual moisture or solvent.

Example 12 (S)-3-[(R)-phenyl-(2,4,6-trifluorophenoxy)methyl]pyrrolidine

A mixture of (S)-3-((S)-hydroxyphenylmethyl)pyrrolidine-1-carboxylicacid t-butyl ester (250 mg, 0.9 mmol), 2,4,6-trifluorophenol (200 mg,1.4 mmol) and PPh₃ (248 mg, 946 μmol) in THF (512 μL, 6.31 mmol) wassonicated for several minutes. While sonicating, DIAD (186 μL, 946 μmol)was added dropwise to the reaction mixture over a couple minutes andsonicated further for 15 minutes. The mixture was concentrated to yieldthe BOC-protected form of the title compound as a yellow oil, which wasused without further purification.

The BOC-protected compound was dissolved in 1.25 M HCl in EtOH (5 mL, 6mmol) and stirred at room temperature for 18 hours, and then evaporatedto dryness. The residue was purified by reverse phase preparative HPLCto afford the title compound as a TFA salt (276 mg, 94% purity). MS m/z:[M+H]⁺ calcd for C₁₇H₁₆F₃NO, 308.12. Found, 308.8. ¹H NMR (400 MHz,DMSO-d₆) δ (ppm): 7.37-7.34 (m, 5H), 7.14 (t, J=8.8, 2H), 5.14 (d,J=8.4, 1H), 3.34-3.31 (m, 1H), 3.23-3.21 (m, 1H), 2.99-2.91 (m, 2H),2.80-2.77 (m, 1H), 2.28-2.25 (m, 1H), 2.13-2.07 (m, 1H).

Example 13(S)-3-[(R)-(2-chloro-6-fluoro-3-methylphenoxy)phenylmethyl]pyrrolidine

A mixture of (S)-3-((S)-hydroxyphenylmethyl)pyrrolidine-1-carboxylicacid t-butyl ester (600 mg, 2 mmol), 2-chloro-6-fluoro-3-methylphenol(521 mg, 3.2 mmol), and PPh₃ (596 mg, 2.3 mmol) in THF (1.2 mL, 15.1mmol) was sonicated for several minutes. While sonicating, DIAD (447 μL,2.3 mmol) was added dropwise to the mixture over a couple minutes andsonicated further for 15 minutes. The mixture was concentrated to yieldthe BOC-protected form of the title compound as a yellow oil, which wasused without further purification.

The BOC-protected compound was dissolved in 1.25 M HCl in EtOH (5 mL, 6mmol) and stirred at room temperature for 18 hours, and then evaporatedto dryness. The residue was purified by reverse phase preparative HPLCto afford the title compound as a TFA salt (350 mg, 94% purity). MS m/z:[M+H]⁺ calcd for C₁₈H₁₉ClFNO, 320.11. Found, 320.3. ¹H NMR (400 MHz,DMSO-d₆) δ (ppm): 7.39-7.30 (m, 5H), 7.05-6.96 (m, 2H), 5.41 (d, J=8.0,1H), 3.40-3.30 (m, 1H), 3.25-3.22 (m, 1H), 3.02-2.95 (m, 2H), 2.79-2.77(m, 1H), 2.27-2.23 (m, 1H), 2.21 (s, 3H), 2.17-2.14-2.10 (m, 1H).

Preparation 6 (R)-3-Formylpyrrolidine-1-carboxylic Acid t-Butyl Ester

To a solution of (R)-Boc-3-pyrrolidinemethanol (5.0 g, 24.8 mmol) in DCMwas added TEMPO (80 mg, 0.5 mmol) and potassium bromide (150 mg, 1.3mmol). This mixture was cooled to 5° C. and vigorously stirred as apre-chilled (at 0° C.) 1:1 mixture of NaOCl in water (53 mL) and asaturated, aqueous NaHCO₃ solution (53 mL) was added dropwise. Theresultant mixture was extracted with DCM (3×50 mL). The combined organiclayers were washed with water (50 mL) and saturated aqueous NaCl (50mL). The organic layer was dried over anhydrous Na₂SO₄ to yield 4.3 g ofthe title compound, which was used without further purification.

Preparation 7 (R)-3-((S)-Hydroxyphenylmethyl)pyrrolidine-1-carboxylicAcid t-Butyl Ester and(R)-3-((R)-Hydroxyphenylmethyl)pyrrolidine-1-carboxylic Acid t-ButylEster

(R)-3-Formylpyrrolidine-1-carboxylic acid t-butyl ester (4.3 g, 22 mmol)in THF (100 mL) was placed in a flask under nitrogen, and the solutionwas cooled to −78° C. 1.0 M of phenylmagnesium bromide in THF (30 mL, 30mmol) was added by syringe over 10 minutes. The solution was stirred at−78° C. for 15 minutes, then placed in an ice bath for 30 minutes.Saturated NH₄Cl (25 mL) was then added. The resulting mixture wasextracted with EtOAc (3×50 mL), and the combined organic layers werewashed with saturated aqueous NaHCO₃ (50 mL) and saturated aqueous NaCl(50 mL), then dried over anhydrous Na₂SO₄ and concentrated to yield 6.1g of product. The mixture of products was purified and separated bypreparative HPLC to yield the title compounds.

Example 14(R)-3-[(S)-(2-chloro-3,6-difluorophenoxy)phenyl-methyl]pyrrolidine

A mixture of (R)-3-((R)-hydroxyphenylmethyl)pyrrolidine-1-carboxylicacid t-butyl ester (10 g, 36.1 mmol), 2-chloro-3,6-difluorophenol (8.9g, 54.1 mmol) and PPh₃ (9.93 g, 37.8 mmol) in THF (20.5 mL, 252 mmol)was sonicated for several minutes. While sonicating, DIAD (7.5 mL, 37.8mmol) was slowly added dropwise to the mixture over several minutes andsonicated further for 15 minutes. The mixture was concentrated and thentriturated in excess hexanes for 16 hours. The PPh₃ oxide precipitatewas filtered off and the organic layer was concentrated to yield ayellow oil. The crude mixture was diluted in EtOAc (300 mL), washed with1N NaOH (2×200 mL) and saturated aqueous NaCl (100 mL). The organiclayer was dried with anhydrous MgSO₄, filtered, and concentrated. Theorganic material was purified by silica gel chromatography (330 gcolumn, 20-50% EtOAc in hexanes) to yield 14 g of(R)-3-[(S)-(2-chloro-3,6-difluorophenoxy)phenylmethyl]pyrrolidine-1-carboxylicacid t-butyl ester as a yellow oil which was used in the next stepwithout further purification.

The oily residue from the previous step was dissolved in 1.25M HCl inEtOH (200 mL, 0.2 mol) and stirred at room temperature for 18 hours, andthen evaporated to dryness to yield a pink solid. The material wastriturated with excess ether for 16 hours with impurities stillremaining. The material was triturated again in excess EtOAc for 2 hoursand filtered to yield 8.43 g of the title compound as amonohydrochloride crystalline salt (8.43 g, 65% yield, 98.6% purity). MSm/z: [M+H]⁺ calcd for C₁₇H₁₆ClF₂NO, 324.09. Found, 324.2. ¹H NMR(DMSO-d₆, 400 MHz) δ (ppm): 7.40-7.32 (m, 5H), 7.26-7.19 (m, 1H),7.13-7.07 (m, 1H), 5.49 (d, J=8.8 Hz, 1H), 3.38-3.34 (obscure, 1H,overlap with solvent), 3.26-3.19 (m, 1H), 3.07-3.02 (m, 1H), 2.99-2.92(m, 1H), 2.81-2.74 (m, 1H), 2.32-2.23 (m, 1H), 2.18-2.08 (m, 1H).

Powder X-Ray Diffraction

A representative PXRD pattern for a sample of this crystalline salt isshown in FIG. 4, and the peak positions are listed in the table below:

2-Theta Angle d-spacing Intensity Relative (Degree) (Å) (Counts)intensity, % 7.28 12.135 1867 15.7 10.70 8.262 512 4.3 14.03 6.309 521343.9 16.10 5.501 8464 71.2 17.99 4.928 4705 39.6 18.80 4.716 9500 79.922.67 3.920 9784 82.3 25.07 3.549 9699 81.6 26.33 3.382 11884 100.028.55 3.124 10098 85.0Thus, this crystalline salt can be characterized by a PXRD patternhaving two or more diffraction peaks at 2θ values selected from 7.3±0.2,10.7±0.2, 14.0±0.2, 16.1±0.2, 18.0±0.2, 18.8±0.2, 22.7±0.2, 25.1±0.2,26.3±0.2, and 28.6±0.2. In particular, crystalline salt can becharacterized by a powder x-ray diffraction pattern comprisingdiffraction peaks at 2θ values of 7.3±0.2, 16.1±0.2, 18.8±0.2, and26.3±0.2.

Thermal Analysis

A representative DSC trace for a sample of this crystallinemonohydrochloric acid salt (FIG. 5) showed that the crystalline salt hasgood thermal stability with the melting peak at about 163.5° C. and nothermal decomposition below 160° C.

A representative TGA trace for a sample of this crystallinemonohydrochloric acid salt showed a loss of solvents and/or water(<0.2%) at temperatures below 150° C., as seen in FIG. 6. This TGA traceindicate that the crystalline salt lost a small amount of weight fromroom temperature to moderately elevated temperatures, which isconsistent with the loss of residual moisture or solvent.

Example 15 (S)-3-[(R)-(4-chloro-2-fluorophenoxy)phenylmethyl]pyrrolidine

Under air, (S)-3-((R)-hydroxyphenylmethyl)pyrrolidine-1-carboxylic acidt-butyl ester (400 mg, 1.4 mmol) and 4-chloro-2-fluoro-1-iodobenzene(374 μL, 2.88 mmol) were dissolved in dry toluene (2.3 mL, 22 mmol). Tothis was added copper(I) iodide (82 mg, 430 μmol), 1,10-phenanthroline(160 mg, 860 μmol), and cesium carbonate (940 mg, 2.9 mmol). Air wasbubbled through the mixture, the vessel was sealed, and the mixture washeated at 105° C. for 48 hours. The mixture was cooled to roomtemperature, rinsed with DCM, filtered, and concentrated to yield theBOC-protected form of the title compound as an oily residue, which wasused without further purification.

The BOC-protected compound was dissolved in 1.25 M HCl in EtOH (9.2 mL,11.5 mmol) and stirred at room temperature for 18 hours, and thenevaporated to dryness. The residue was purified by reverse phasepreparative HPLC to afford the title compound as a TFA salt (214 mg, 97%purity). MS m/z: [M+H]⁺ calcd for C₁₇H₁₇ClFNO, 306.10. Found, 306.4. ¹HNMR (400 MHz, DMSO-d₆) δ (ppm): 7.43-7.39 (m, 5H), 7.34-7.31 (m, 1H),7.10-7.07 (m, 1H), 7.00-6.96 (m, 1H), 5.46 (d, J=6.8, 1H), 3.35-3.28 (m,1H), 3.26-3.17 (m, 1H), 3.10-3.05 (m, 1H), 2.92-2.83 (m, 2H), 2.10-2.07(m, 1H), 2.00-1.97 (m, 1H).

Example 16 (R)-3-[(S)-(3,5-Dichlorophenoxy)phenylmethyl]pyrrolidine

Under air, (R)-3-((S)-hydroxyphenylmethyl)pyrrolidine-1-carboxylic acidt-butyl ester (400 mg, 1 mmol) and 1,3-dichloro-5-iodobenzene (787 mg,2.88 mmol) were dissolved in dry toluene (2.3 mL, 22 mmol). To this wasadded copper(I) iodide (82 mg, 430 μmol), 1,10-phenanthroline (160 mg,0.86 mmol), and cesium carbonate (940 mg, 2.9 mmol). Air was bubbledthrough the mixture, the vessel was sealed, and the mixture was heatedat 105° C. for 48 hours. The mixture was cooled to room temperature,rinsed with DCM, filtered, and concentrated to yield the BOC-protectedform of the title compound((R)-3-[(S)-(3,5-dichlorophenoxy)phenylmethyl]pyrrolidine-1-carboxylicacid t-butyl ester) as an oily residue, which was used without furtherpurification.

The BOC-protected compound was dissolved in 1.25 M HCl in EtOH (9.2 mL,11.5 mmol) and stirred at room temperature for 18 hours, and thenevaporated to dryness. The residue was purified by reverse phasepreparative HPLC to afford the title compound as a TFA salt (258 mg, 91%purity). MS m/z: [M+H]⁺ calcd for C₁₇H₁₇Cl₂NO, 322.07. Found, 322.0.

Alternate Method

(R)-3-((S)-hydroxyphenylmethyl)pyrrolidine-1-carboxylic acid t-butylester (10.0 g, 36.0 mmol) was dissolved in anhydrous DMF (65 mL, 840mmol). Washed and dried sodium hydride (1.0 g, 43 mmol) was added, andthe mixture stirred at room temperature for 15 minutes.3,5-Dichlorofluorobenzene (10 mL, 80 mmol) was then added, and themixture stirred at 70° C. for 3 hours. The mixture was cooled to roomtemperature. EtOAc (200 mL) and 1M HCl (200 mL) was added, mixed, andthe phases separated. The organic layer was washed with 2×200 mL ofdiluted aqueous NaCl, dried over Na₂SO₄, and concentrated to dryness toyield 19 g of crude product. The crude product was purified on a 300 gSiG column to yield(R)-3-[(S)-(3,5-dichlorophenoxy)phenylmethyl]pyrrolidine-1-carboxylicacid t-butyl ester as a white sticky foam (14.1 g, 91.67% purity).

Monohydrochloride Crystalline Salt

(R)-3-[(S)-(3,5-dichlorophenoxy)phenylmethyl]pyrrolidine-1-carboxylicacid t-butyl ester (14.0 g, 33.1 mmol) was dissolved in EtOH (100 mL, 2mol). Into the mixture was added an HCl solution prepared by the slowaddition of acetyl chloride (23.6 mL, 331 mmol) into EtOH (50 mL, 860mmol) at 0° C. The mixture was stirred at room temperature overnight.The solvent was removed by rotary evaporation, EtOAc (200 mL) was added,followed by removal of most of the solvent. EtOAc (50 mL) was added, thesolution was heated to 75° C. for 15 minutes, cooled to roomtemperature, filtered and dried to yield(R)-3-[(S)-(3,5-dichlorophenoxy)phenylmethyl]pyrrolidine as an HCl salt(10.5 g, >99% purity).

(R)-3-[(S)-(3,5-dichlorophenoxy)phenylmethyl]pyrrolidine-1-carboxylicacid t-butyl ester (14.0 g, 33.1 mmol) was dissolved in EtOH (100 mL, 2mol). Into the mixture was added an HCl solution prepared by the slowaddition of acetyl chloride (23.6 mL, 331 mmol) into EtOH (50 mL, 860mmol) at 0° C. The mixture was stirred at room temperature overnight.The solvent was removed by rotary evaporation, EtOAc (200 mL) was added,followed by removal of most of the solvent. EtOAc (100 mL) was added,the solution was heated to 75° C. for 15 minutes, cooled to roomtemperature (seeded at 35° C.) and stirred for 2 hours. The solids werefiltered off and dried to yield 5 g of product. The product was slurriedtwice in 65° C. EtOAc (5 vol) to yield(R)-3-[(S)-(3,5-dichlorophenoxy)phenylmethyl]pyrrolidine as an HCl salt(4.1 g, >99% purity).

(R)-3-(S)-hydroxyphenylmethyl)pyrrolidine-1-carboxylic acid t-butylester (2.0 g, 7.2 mmol) was dissolved in anhydrous DMF (10 mL, 100mmol). Lithium hydride (86 mg, 11 mmol) was added in 3 separateportions. The mixture was stirred at room temperature for 15 minutes.Into the mixture was added 3,5-dichlorofluorobenzene (1.7 mL, 14 mmol),and the resultant mixture stirred at room temperature for 15 minutes.The mixture was then stirred at 70° C. overnight. The mixture was cooledto room temperature, and EtOAc (80 mL) and 1M HCl (50 mL) were added.After mixing, the phases were separated and the organic layer was washedwith diluted aqueous NaCl (1×50 mL), dried over Na₂SO₄, and concentratedto dryness to yield 3.5 g of crude product. Into the crude product wasadded 25 mL cold HCl in an EtOH/EtOAc solution and stirred at roomtemperature for 3 hours. Most of the solvent was removed by rotaryevaporation, EtOAc was added (50 mL) and most of the solvent was removedagain. Recrystallization and reslurry from EtOAc (20 mL) gave(R)-3-[(S)-(3,5-dichlorophenoxy)phenylmethyl]pyrrolidine as an HCl salt(2 g, ˜99% purity).

The three batches of(R)-3-[(S)-(3,5-dichlorophenoxy)phenylmethyl]pyrrolidine.HCl (16.5 g,46.0 mmol) was suspended in EtOAc (100 mL, 1 mol) and then stirred atroom temperature for 2 hours, filtered and dried in vacuum over 48 hoursto yield (R)-3-[(S)-(3,5-dichlorophenoxy)phenylmethyl]pyrrolidine as amonohydrochloride crystalline salt (16.2 g).

Powder X-Ray Diffraction

The PXRD pattern for the monohydrochloride salt showed the material tobe crystalline. A representative PXRD pattern for a sample of thiscrystalline salt is shown in FIG. 7, and the peak positions are listedin the table below:

2-Theta Angle d-spacing Intensity Relative (Degree) (Å) (Counts)intensity, % 5.99 14.740 331 2.2 12.92 6.847 2631 17.3 16.04 5.522 10306.8 18.97 4.673 2168 14.2 19.73 4.496 15244 100.0 21.20 4.188 4561 29.922.97 3.869 6526 42.8 23.39 3.799 7382 48.4 23.87 3.725 7756 50.9 33.682.659 6007 39.4Thus, this crystalline salt can be characterized by a PXRD patternhaving two or more diffraction peaks at 2θ values selected from 6.0±0.2,12.9±0.2, 16.0±0.2, 19.0±0.2, 19.7±0.2, 21.2±0.2, 23.0±0.2, 23.4±0.2,23.9±0.2, and 33.7±0.2. In particular, crystalline salt can becharacterized by a powder x-ray diffraction pattern comprisingdiffraction peaks at 2θ values of 12.9±0.2, 19.7±0.2, 23.4±0.2, and23.9±0.2.

Thermal Analysis

A representative DSC trace for a sample of this crystallinemonohydrochloric acid salt (FIG. 8) showed that the crystalline salt hasgood thermal stability with the melting peak at about 223.0° C. and nothermal decomposition below 220° C.

A representative TGA trace for a sample of this crystallinemonohydrochloric acid salt showed a loss of solvents and/or water(<0.1%) at temperatures below 150° C., as seen in FIG. 8. This TGA traceindicate that the crystalline salt lost a small amount of weight fromroom temperature to moderately elevated temperatures, which isconsistent with the loss of residual moisture or solvent.

Preparation 8 3-(Methoxymethylcarbamoyl)pyrrolidine-1-carboxylic Acidt-Butyl Ester

Pyrrolidine-1,3-dicarboxylic acid 1-t-butyl ester (0.7 g, 3.3 mmol),HCTU (2.0 g, 4.9 mmol), and HOBt (747 mg, 4.9 mmol),N,O-dimethylhydroxylamine HCl (1.6 g, 16.3 mmol) and DMF (10.0 mL, 129mmol) were combined and cooled at 0° C. using an ice bath. DIPEA (5.7mL, 32.5 mmol) was added slowly over 5 minutes. The mixture was allowedto warm to room temperature and stirred for 15 hours. The mixture wasthen diluted with sat. NaHCO₃ (75 mL) and extracted with EtOAc (2×100mL). The combined organic layers were washed with sat. NaCl (50 mL),dried over Na₂SO₄, filtered, concentrated under high vacuum to yield 2.9g of the crude title compound as a mixture of the (R) and (S)enantiomers.

Preparation 9 3-Benzoylpyrrolidine-1-carboxylic Acid t-Butyl Ester

3-(Methoxymethylcarbamoyl)pyrrolidine-1-carboxylic acid t-butyl ester(400 mg, 1.6 mmol) and THF (10 mL, 0.1 mol) were combined undernitrogen. The solution was cooled at 0° C. using an ice bath. 1.0 M ofPhenylmagnesium bromide in THF (2.0 mL, 2.0 mol) was added dropwise over5 minutes. The mixture was slowly warmed to room temperature and stirredfor 2 hours, at which point an additional amount of 1.0 M ofphenylmagnesium bromide in THF (5.0 mL, 5.0 mol) was added over 10minutes. After 5 minutes, the mixture was cooled in an ice bath and thereaction quenched by the slow addition of water (15 mL). The mixture wasextracted with EtOAc (1×100 mL), and the organic layer was washed withsaturated aqueous NaCl (50 mL), dried over Na₂SO₄, filtered, andconcentrated to yield 850 mg of crude product, which was purified byflash chromatography (12 g column, 20-100% EtOAc in hexanes over 17minutes) to yield a mixture of the (R) and (S) enantiomers of the titlecompound as a clear oil (412 mg).

Preparation 10 (S)-3-(Methoxymethylcarbamoyl)pyrrolidine-1-carboxylicAcid tert-Butyl Ester

(3S)-Boc-β-Proline-OH (700 mg, 3.3 mmol;(S)-pyrrolidine-1,3-dicarboxylic acid 1-t-butyl ester), HCTU (1.7 g, 4.1mmol), HOBt (622 mg, 4.1 mmol), N,O-dimethyl-hydroxylamine HCl (1.6 g,16.3 mmol), and DMF (10.0 mL, 129 mmol) were combined and cooled at 0°C. using an ice bath. DIPEA (5.7 mL, 32.5 mmol) was added slowly over 5minutes. The mixture was allowed to warm to room temperature and stirredfor 15 hours. The mixture was then diluted with saturated NaHCO₃ (75 mL)and extracted with EtOAc (2×100 mL). The combined organic layers werewashed with saturated aqueous NaCl (50 mL) and water (50 mL), dried overNa₂SO₄, filtered, and concentrated under high vacuum to yield 1.6 g ofthe crude title compound.

Preparation 11 (R)-3-(Methoxymethylcarbamoyl)pyrrolidine-1-carboxylicAcid t-Butyl Ester

(R)-1-N-Boc-β-Proline (700 mg, 3.3 mmol;(R)-pyrrolidine-1,3-dicarboxylic acid 1-t-butyl ester), HCTU (1.7 g, 4.1mmol), HOBt (622 mg, 4.1 mmol), N,O-dimethyl-hydroxylamine HCl (1.6 g,16.3 mmol) and DMF (10.0 mL, 129 mmol) were combined and cooled at 0° C.using an ice bath. DIPEA (5.7 mL, 32.5 mmol) was added slowly over 5minutes. The mixture was allowed to warm to room temperature and stirredfor 15 hours. The mixture was then diluted with sat. NaHCO₃ (75 mL) andextracted with EtOAc (2×100 mL). The combined organic layers were washedwith sat. NaCl (50 mL) and water (50 mL), dried over Na₂SO₄, filtered,and concentrated under high vacuum to yield 1.6 g of the crude product,which was purified by flash chromatography (12 g column, 10-100% EtOAcin hexanes over 16 minutes), and placed under high vacuum for 15 minutesto yield 723 mg of the title compound.

Preparation 12 (S)-3-Benzoylpyrrolidine-1-carboxylic Acid t-Butyl Ester

(S)-3-(Methoxymethylcarbamoyl)pyrrolidine-1-carboxylic acid t-butylester (400 mg, 1.6 mmol) and THF (10 mL, 0.1 mol) were combined undernitrogen. The solution was cooled at 0° C. using an ice bath. 1.0 M ofPhenylmagnesium bromide in THF (7.0 mL, 7.0 mmol) was added dropwiseover 5 minutes. The mixture was slowly warmed to room temperature andstirred for 30 minutes. The mixture was cooled in an ice bath and thereaction was quenched by the slow addition of water (15 mL). The mixturewas extracted with EtOAc (1×100 mL), and the organic layer was washedwith sat. NaCl (50 mL), dried over Na₂SO₄, filtered, and concentrated toyield 849 mg of crude product, which was purified by flashchromatography (12 g column, 20-100% EtOAc in hexanes over 17 minutes),and placed under high vacuum for 15 minutes to yield 372 mg of the titlecompound as a clear oil.

Example 17 RS/SR mixture of enantiomers (17-1) and SS/RR mixture ofenantiomers (17-2) of 3-(Phenoxyphenylmethyl)pyrrolidine

Following the procedure of Example 1 and using3-(phenoxyphenylmethyl)-pyrrolidine-1-carboxylic acid t-butyl ester inplace of 3-(phenyl-o-tolyloxymethyl)-pyrrolidine-1-carboxylic acidt-butyl ester, the RS/SR mixture of enantiomers (16-1) of the titlecompound was prepared as an HCl salt (56% yield; 98% purity). MS m/z:[M+H]⁺ calcd for C₁₇H₁₉NO, 254.15. Found 254.1.

Following the procedure of Example 2, and, in Preparation 3,substituting the RS/SR mixture of enantiomers with the SS/RR mixture ofenantiomers of 3-(hydroxyphenylmethyl)-pyrrolidine-1-carboxylic acidt-butyl ester (47.5 mg, 170 μmol), and substituting 2-iodoanisole withthe appropriate aryl iodide, the SS/RR mixture of enantiomers (16-2) ofthe title compound was prepared (12.4 mg) as a TFA salt. MS m/z: [M+H]⁺calcd for C₁₇H₁₉NO, 254.15. Found 254.2.

While both of the aforementioned compounds exhibit affinity for SERT andNET, compound 17-1 exhibits a NET pK_(i)≧8 and a SERT K_(i)/NET K_(i) inthe range of 0.1-100.

Cmpd. NET pK_(i) SERT K_(i)/NET K_(i) Ex. 17-1 8.2 1.3

In the following figures, the two chiral centers are identified by the *and ** symbols. When describing the stereochemistry, the carbon atomindicated by the * symbol is designated first. Thus, an “SR” designationrepresents a compound having the (S) configuration at the carbon atomindicated by the * symbol and having the (R) configuration at the **carbon atom. The same hold true for racemic mixtures. For example, an“RS/SR” designation represents a racemic mixture of (R,S) compounds and(S,R) compounds, i.e., a mixture of compounds having the (R)configuration at the * carbon atom and the (S) configuration at the **carbon atom and compounds having the (S) configuration at the * carbonatom and the (R) configuration at the ** carbon atom.

Example 18

Following the procedures described in the examples above, andsubstituting the appropriate starting materials and reagents, compounds18-1 to 18-7, having formula II′, were also prepared:

(II′)

MS m/z: Stereo- [M + H]⁺ Cmpd. chemistry R¹ Formula calcd found 18-1RS/SR 2-F C₁₇H₁₈FNO 272.14 272.2 18-2 SR/RS 3-Cl C₁₇H₁₈ClNO 288.11 288.018-3 SR/RS 3-CH₃ C₁₈H₂₁NO 268.16 268.2 18-4 RS/SR 3-OCH₃ C₁₈H₂₁NO₂284.16 284.2 18-5 RS/SR 3-OCF₃ C₁₈H₁₈F₃NO₂ 338.13 338.2 18-6 SR/SS3-CH₂OH C₁₈H₂₁NO₂ 284.16 284.4 18-7 SR/SS 3-CHO C₁₈H₁₉NO₂ 282.14 282.8While all the aforementioned compounds exhibit affinity for both SERTand NET, the compound listed in the table below exhibits a NET pK_(i)≧8and a SERT K_(i)/NET K_(i) in the range of 0.1-100.

Cmpd. NET pK_(i) SERT K_(i)/NET K_(i) 18-7 8 6.3

Example 19

Following the procedures described in the examples above, andsubstituting the appropriate starting materials and reagents, compounds19-1 to 19-31 having the following formula, were also prepared:

(III)

MS m/z: Stereo- [M + H]⁺ Cmpd. chemistry R² Formula calcd found 19-1RS/SR F C₁₇H₁₈FNO 272.14 272.6 19-2 SR F C₁₇H₁₈FNO 272.14 272.2 19-3 RSF C₁₇H₁₈FNO 272.14 272.2 19-4 RS/SR Cl C₁₇H₁₈ClNO 288.11 288.0 19-5 SRCl C₁₇H₁₈ClNO 288.11 288.0 19-6 RS Cl C₁₇H₁₈ClNO 288.11 288.0 19-7 RS/SRBr C₁₇H₁₈BrNO 332.06 332.0 19-8 RS/SR I C₁₇H₁₈INO 380.04 380.4 Ex. 1RS/SR —CH₃ C₁₈H₂₁NO 268.16 268.1 Ex. 4-1 SS/RR —CH₃ C₁₈H₂₁NO 268.16268.2 19-9 SR —CH₃ C₁₈H₂₁NO 268.16 268.2 19-10 RS —CH₃ C₁₈H₂₁NO 268.16268.2 19-11 RS/SR —CH₂CH₃ C₁₉H₂₃NO 282.18 282.2 19-12 RS/SR —CH(CH₃)₂C₂₀H₂₅NO 296.19 296.2 19-13 RS/SR —CF₃ C₁₈H₁₈F₃NO 322.13 322.2 Ex. 2RS/SR —OCH₃ C₁₈H₂₁NO₂ 284.16 284.4 Ex. 6-1 RS —OCH₃ C₁₈H₂₁NO₂ 284.16284.4 Ex. 6-2 SR —OCH₃ C₁₈H₂₁NO₂ 284.16 284.4 Ex. 4-2 SS/RR —OCH₃C₁₈H₂₁NO₂ 284.16 284.4 19-14 RR —OCH₃ C₁₈H₂₁NO₂ 284.16 284.8 19-15 SS—OCH₃ C₁₈H₂₁NO₂ 284.16 284.8 19-16 SS/RR —OCH₂CH₃ C₁₉H₂₃NO₂ 298.17 298.6Ex. 5 RS/SR —OCH₂CH₃ C₁₉H₂₃NO₂ 298.17 298.6 19-17 RS/SR —OCH(CH₃)₂C₂₀H₂₅NO₂ 312.19 312.4 19-18 RS/SR —OCF₃ C₁₈H₁₈F₃NO₂ 338.13 338.2 19-19RS/SR -phenyl C₂₃H₂₃NO 330.18 330.2 19-20 RR/SS —CH₂-phenyl C₂₄H₂₅NO344.19 344.2 19-21 RS/SR —CH₂-phenyl C₂₄H₂₅NO 344.19 344.2 19-22 RS/SR—O-2,4- C₂₃H₂₁Cl₂NO₂ 414.10 414.0 dichlorophenyl 19-23 RS/SR —O-benzylC₂₄H₂₅NO₂ 360.19 360.2 19-24 RS/SR —CH₂OH C₁₈H₂₁NO₂ 284.16 284.2 Ex. 9-3SR —C(O)CH₃ C₁₉H₂₁NO₂ 296.16 296.2 19-25 RS —C(O)CH₃ C₁₉H₂₁NO₂ 296.16296.2 19-26 SR/RS —C(O)CH₂CH₃ C₂₀H₂₃NO₂ 310.17 310.2 19-27 SR—C(O)CH₂CH₃ C₂₀H₂₃NO₂ 310.17 310.2 Ex. 9-5 SR —C(O)OCH₃ C₁₉H₂₁NO₃ 312.15312.2 19-28 RS/SR —NO₂ C₁₇H₁₈N₂O₃ 299.13 299.2 19-29 RS/SR —SCH₃C₁₈H₂₁NOS 300.13 300.2 19-30 SR —SCH₃ C₁₈H₂₁NOS 300.13 300.4 19-31 RS—SCH₃ C₁₈H₂₁NOS 300.13 300.4 Ex. 9-1 SR —SO₂CH₃ C₁₈H₂₁NO₃S 332.12 332.0While all the aforementioned compounds exhibit affinity for both SERTand NET, the compounds listed in the table below exhibit a NET pK_(i)≧8and a SERT K_(i)/NET K_(i) in the range of 0.1-100.

Cmpd. NET pK_(i) SERT K_(i)/NET K_(i) 19-1 8.6 4 19-2 9 63 19-3 8 0.419-4 9.1 2 19-5 9.3 65 19-6 8.2 0.2 19-7 9 1 19-8 9 0.6 Ex. 1 8.5 1.319-9 9.1 13 19-11 8.5 4 19-12 8.7 16 19-13 8.6 7.9 Ex. 2 9.1 13 Ex. 6-29.4 50 Ex. 5 8.9 32 19-17 8.5 40 19-18 8.9 20 19-19 8.7 32 19-20 8.1 1.619-21 8.3 5 19-23 8 3.2 Ex. 9-3 8.5 50 19-26 8.4 50 19-27 8.7 100 19-288.4 13 19-29 9.2 25 19-30 9.4 63

Example 20

Following the procedures described in the examples above, andsubstituting the appropriate starting materials and reagents, compounds20-1 to 20-39 having the following formula, were also prepared:

(III′)

MS m/z: Stereo- [M + H]⁺ Cmpd. chemistry R¹ R² Formula calcd found 20-1RS/SR 2-Cl Cl C₁₇H₁₇Cl₂NO 322.07 322.0 20-2 RR/SS 2-Cl Cl C₁₇H₁₇Cl₂NO322.07 322.0 20-3 RS/SR 2-F Cl C₁₇H₁₇ClFNO 306.10 306.0 20-4 RS/SR 3-FCl C₁₇H₁₇ClFNO 306.10 306.0 20-5 RS/SR 3-Cl Cl C₁₇H₁₇Cl₂NO 322.07 322.020-6 RS/SR 3-CH₃ Cl C₁₈H₂₀ClNO 302.12 302.2 20-7 RS/SR 3-OCH₃ ClC₁₈H₂₀ClNO₂ 318.12 318.2 20-8 RS/SR 2-OCF₃ Cl C₁₈H₁₇ClF₃NO₂ 372.09 372.020-9 RS/SR 3-OCF₃ Cl C₁₈H₁₇ClF₃NO₂ 372.09 372.0 20-10 RS/SR 3-OCH₃—CH(CH₃)₂ C₂₁H₂₇NO₂ 326.20 326.2 20-11 RS/SR 3-OCF₃ —CH(CH₃)₂C₂₁H₂₄F₃NO₂ 380.18 380.2 20-12 RS/SR 3-Cl —CH(CH₃)₂ C₂₀H₂₄ClNO 330.15330.2 20-13 RS/SR 3-F —CH(CH₃)₂ C₂₀H₂₄FNO 314.18 314.2 20-14 RS/SR 2-F—OCH₃ C₁₈H₂₀FNO₂ 302.15 302.2 20-15 RS/SR 3-F —OCH₃ C₁₈H₂₀FNO₂ 302.15302.2 20-16 RS/SR 2-Cl —OCH₃ C₁₈H₂₀ClNO₂ 318.12 318.2 20-17 SR 2-Cl—OCH₃ C₁₈H₂₀ClNO₂ 318.12 318.0 20-18 RS 2-Cl —OCH₃ C₁₈H₂₀ClNO₂ 318.12318.0 20-19 RR/SS 2-Cl —OCH₃ C₁₈H₂₀ClNO₂ 318.12 318.2 20-20 RS/SR 3-Cl—OCH₃ C₁₈H₂₀ClNO₂ 318.12 318.2 20-21 RS/SR 4-Cl —OCH₃ C₁₈H₂₀ClNO₂ 318.12318.2 20-22 SR/RS 3-OCH₃ —OCH₃ C₁₉H₂₃NO₃ 314.17 314.2 20-23 RS/SR 2-OCF₃—OCH₃ C₁₉H₂₀F₃NO₃ 368.14 368.2 20-24 RR/SS 2-OCF₃ —OCH₃ C₁₉H₂₀F₃NO₃368.14 368.2 20-25 RS/SR 3-OCF₃ —OCH₃ C₁₉H₂₀F₃NO₃ 368.14 368.2 20-26SR/SS 3-CH₂OH —OCH₃ C₁₉H₂₃NO₃ 314.17 314.0 20-27 SR 3-CN —OCH₃C₁₉H₂₀N₂O₂ 309.15 309.8 20-28 SR 4-CN —OCH₃ C₁₉H₂₀N₂O₂ 309.15 309.820-29 SR 2-SO₂CH₃ —OCH₃ C₁₉H₂₃NO₄S 362.13 362.0 20-30 SR 3-CONH₂ —OCH₃C₁₉H₂₂N₂O₃ 327.16 327.4 20-31 RR/SS 3,5-F —OCH₃ C₁₈H₁₉F₂NO₂ 320.14 320.220-32 RS/SR 3,5-F —OCH₃ C₁₈H₁₉F₂NO₂ 320.14 320.2 20-33 SR 3,5-F —OCH₃C₁₈H₁₉F₂NO₂ 320.14 320.0 20-34 RS 3,5-F —OCH₃ C₁₈H₁₉F₂NO₂ 320.14 320.220-35 RS/SR 3-F,5-Cl —OCH₃ C₁₈H₁₉ClFNO₂ 336.11 336.0 20-36 RS/SR3-F,5-CH₃ —OCH₃ C₁₉H₂₂FNO₂ 316.16 316.2 20-37 RR/SS 3-F,5-CH₃ —OCH₃C₁₉H₂₂FNO₂ 316.16 316.2 20-38 RS/SR 3-Cl, 5-CF₃ —OCH₃ C₁₉H₁₉ClF₃NO₂386.11 386.0 20-39 RS/SR 3,5-diF Ph C₂₃H₂₁F₂NO 366.16 366.2While all the aforementioned compounds exhibit affinity for both SERTand NET, the compounds listed in the table below exhibit a NET pK_(i)≧8and a SERT K_(i)/NET K_(i) in the range of 0.1-100.

Cmpd. NET pK_(i) SERT K_(i)/NET K_(i) 20-1 8.5 0.5 20-4 8.6 0.63 20-58.6 1.6 20-6 8.4 1.6 20-7 8.5 1.3 20-10 8.3 2.5 20-12 8.3 7.9 20-13 8.310 20-15 8.3 4 20-16 8.9 4 20-17 9 13 20-20 8.6 13 20-21 8.7 4 20-23 8.31.6 20-26 8.4 10 20-27 9.1 100 20-28 8.6 5 20-30 8.6 25 20-31 8.3 6.320-32 9.1 10 20-34 8.4 1 20-35 9.2 16 20-36 8.9 7.9 20-37 8.2 13

Example 21

Following the procedures described in the examples above, andsubstituting the appropriate starting materials and reagents, compounds21-1 to 21-21, having the following formula, were also prepared:

(IV)

MS m/z: Stereo- [M + H]⁺ Cmpd. chemistry R³ Formula calcd found 21-1RS/SR F C₁₇H₁₈FNO 272.14 272.2 21-2 RS/SR Cl C₁₇H₁₈ClNO 288.11 288.221-3 SR Cl C₁₇H₁₈ClNO 288.11 288.0 21-4 RS Cl C₁₇H₁₈ClNO 288.11 288.021-5 RS/SR Br C₁₇H₁₈BrNO 332.06 332.0 21-6 RS/SR I C₁₇H₁₈INO 380.04380.2 21-7 RS/SR —CH₃ C₁₈H₂₁NO 268.16 268.2 21-8 SR —CH₃ C₁₈H₂₁NO 268.16268.2 21-9 RS —CH₃ C₁₈H₂₁NO 268.16 268.2 21-10 RS/SR —CF₃ C₁₈H₁₈F₃NO322.13 322.2 21-11 RS/SR —OCH₃ C₁₈H₂₁NO₂ 284.16 284.2 21-12 RS/SR —OCF₃C₁₈H₁₈F₃NO₂ 338.13 338.2 21-13 RS/SR

C₂₃H₂₃NO₂ 346.17 346.2 21-14 RS/SR

C₂₃H₂₂ClNO₂ 380.13 380.2 21-15 RS/SR

C₂₃H₂₂FNO₂ 364.16 364.2 21-16 RS/SR

C₂₃H₂₂ClNO₂ 380.13 380.2 21-17 RS/SR

C₂₅H₂₇NO₂ 374.20 374.2 21-18 RS/SR

C₂₅H₂₇NO₃ 390.20 390.2 21-19 RS/SR

C₂₅H₂₇NO₂ 374.20 374.2 21-20 RS/SR

C₂₅H₂₇NO₃ 390.20 390.2 21-21 RS/SR

C₂₄H₂₅NO₂ 360.19 360.2 Ex. 9-2 SR —NO₂ C₁₇H₁₈N₂O₃ 299.13 299.2While all the aforementioned compounds exhibit affinity for both SERTand NET, the compounds listed in the table below exhibit a NET pK_(i)≧8and a SERT K_(i)/NET K_(i) in the range of 0.1-100.

Cmpd. NET pK_(i) SERT K_(i)/NET K_(i) 21-1 8.4 1 21-2 8.6 0.3 21-3 8.6 221-4 8.3 0.1 21-5 8.5 0.2 21-6 8.4 0.2 21-7 8.4 0.5 21-8 8.2 2.5 21-138.9 1.3 21-14 8.3 0.8 21-15 8.7 1 21-16 8.2 0.3

Example 22

Following the procedures described in the examples above, andsubstituting the appropriate starting materials and reagents, compounds22-1 to 22-8, having the following formula, were also prepared:

(IV′)

Stereo- MS m/z: chemis- [M + H]⁺ Cmpd. try R¹ R³ Formula calcd found22-1 SR 3-SO₂CH₃, F C₁₈H₁₉F₂NO₃S 368.11 368.0 5-F 22-2 RS/SR 2-F ClC₁₇H₁₇ClFNO 306.10 306.0 22-3 RS/SR 3-F Cl C₁₇H₁₇ClFNO 306.10 306.0 22-4RS/SR 3-Cl Cl C₁₇H₁₇C₁₂NO 322.07 322.0 22-5 RS/SR 2-CH₃ Cl C₁₈H₂₀ClNO302.12 302.2 22-6 RS/SR 3-CH₃ Cl C₁₈H₂₀ClNO 302.12 302.2 22-7 RS/SR3-OCH₃ Cl C₁₈H₂₀ClNO₂ 318.12 318.2 22-8 RS/SR 3-OCF₃ Cl C₁₈H₁₇ClF₃NO₂372.09 372.0While all the aforementioned compounds exhibit affinity for both SERTand NET, the compound listed in the table below exhibits a NET pK_(i)≧8and a SERT K_(i)/NET K_(i) in the range of 0.1-100.

Cmpd. NET pK_(i) SERT K_(i)/NET K_(i) 22-3 8.1 0.1 22-4 8.1 0.2

Example 23

Following the procedures described in the examples above, andsubstituting the appropriate starting materials and reagents, compounds23-1 to 23-17, having the following formula, were also prepared:

(V)

MS m/z: Stereo- [M + H]⁺ Cmpd. chemistry R⁴ Formula calcd found 23-1RS/SR F C₁₇H₁₈FNO 272.14 272.2 23-2 RS/SR Cl C₁₇H₁₈ClNO 288.11 288.223-3 SR Cl C₁₇H₁₈ClNO 288.11 288.0 23-4 RS Cl C₁₇H₁₈ClNO 288.11 288.023-5 RS/SR Br C₁₇H₁₈BrNO 332.06 332.0 23-6 RS/SR —CH₃ C₁₈H₂₁NO 268.16268.2 23-7 SR —CH₃ C₁₈H₂₁NO 268.16 268.2 23-8 RS —CH₃ C₁₈H₂₁NO 268.16268.2 23-9 RS/SR —CF₃ C₁₈H₁₈F₃NO 322.13 322.2 23-10 RS/SR —OCH₃C₁₈H₂₁NO₂ 284.16 284.2 23-11 RS/SR —OCH₂CH₃ C₁₉H₂₃NO₂ 298.17 298.2 23-12RS/SR —OCF₃ C₁₈H₁₈F₃NO₂ 338.13 338.2 23-13 RS/SR -Ph C₂₃H₂₃NO 330.18330.2 23-14 RS/SR —O-Ph C₂₃H₂₃NO₂ 346.17 346.2 23-15 RS/SR —OCH₂-PhC₂₄H₂₅NO₂ 360.19 360.2 23-16 SR —SO₂CH₃ C₁₈H₂₁NO₃S 332.12 332.2 23-17 SR—CONH₂ C₁₈H₂₀N₂O₂ 297.15 297.2While all the aforementioned compounds exhibit affinity for both SERTand NET, the compounds listed in the table below exhibit a NET pK_(i)≧8and a SERT K_(i)/NET K_(i) in the range of 0.1-100.

Cmpd. NET pK_(i) SERT K_(i)/NET K_(i) 23-3 8.4 0.2 23-6 8.2 0.2 23-158.1 2

Example 24

Following the procedures described in the examples above, andsubstituting the appropriate starting materials and reagents, compounds24-1 to 24-7, having the following formula, were also prepared:

(V′)

Stereo- MS m/z: chemis- [M + H]⁺ Cmpd. try R¹ R⁴ Formula calcd found24-1 RS/SR 2-F Cl C₁₇H₁₇ClFNO 306.10 306.0 24-2 RS/SR 3-F Cl C₁₇H₁₇ClFNO306.10 306.0 24-3 RS/SR 3-Cl Cl C₁₇H₁₇Cl₂NO 322.07 322.0 24-4 RS/SR2-CH₃ Cl C₁₈H₂₀ClNO 302.12 302.2 24-5 RS/SR 3-CH₃ Cl C₁₈H₂₀ClNO 302.12302.2 24-6 RS/SR 3-OCH₃ Cl C₁₈H₂₀ClNO₂ 318.12 318.2 24-7 RS/SR 3-OCF₃ ClC₁₈H₁₇ClF₃NO₂ 372.09 372.0The aforementioned compounds exhibit affinity for both SERT and NET.

Example 25

Following the procedures described in the examples above, andsubstituting the appropriate starting materials and reagents, compounds25-1 to 25-34, having the following formula, were also prepared:

(VI)

MS m/z: Stereo- [M + H]⁺ Cmpd. chemistry R² R³ Formula calcd found 25-1SR F F C₁₇H₁₇F₂NO 290.13 290.2 25-2 RS F F C₁₇H₁₇F₂NO 290.13 290.2 25-3RS/SR F Cl C₁₇H₁₇ClFNO 306.10 306.6 25-4 SR F Cl C₁₇H₁₇ClFNO 306.10306.0 25-5 RS F Cl C₁₇H₁₇ClFNO 306.10 306.0 25-6 SR F —CF₃ C₁₈H₁₇F₄NO340.12 340.0 25-7 RS F —CF₃ C₁₈H₁₇F₄NO 340.12 340.0 25-8 RS/SR F —O-PhC₂₃H₂₂FNO₂ 364.16 364.2 25-9 RS/SR Cl Cl C₁₇H₁₇Cl₂NO 322.07 322.0 25-10RS Cl Cl C₁₇H₁₇Cl₂NO 322.07 322.0 25-11 SR Cl Cl C₁₇H₁₇Cl₂NO 322.07322.0 25-12 SS Cl Cl C₁₇H₁₇Cl₂NO 322.07 322.0 25-13 RR Cl Cl C₁₇H₁₇Cl₂NO322.07 322.0 Ex. 9-4 SR Cl F C₁₇H₁₇ClFNO 306.10 306.0 25-14 RS Cl FC₁₇H₁₇ClFNO 306.10 306.2 25-15 RS/SR Cl —O-Ph C₂₃H₂₂ClNO₂ 380.13 380.025-16 SR Cl —CF₃ C₁₈H₁₇ClF₃NO 356.10 356.0 25-17 RS/SR —CH₃ F C₁₈H₂₀FNO286.15 286.2 25-18 RS —CH₃ F C₁₈H₂₀FNO 286.15 286.2 25-19 SR —CH₃ FC₁₈H₂₀FNO 286.15 286.2 25-20 RS/SR —CH₃ Cl C₁₈H₂₀ClNO 302.12 302.2 25-21SR —CH₃ Cl C₁₈H₂₀ClNO 302.12 302.0 25-22 RS —CH₃ Cl C₁₈H₂₀ClNO 302.12302.0 25-23 RS/SR —CH₃ —CH₃ C₁₉H₂₃NO 282.18 282.2 25-24 SR —CH₃ —CH₃C₁₉H₂₃NO 282.18 282.2 25-25 RS —CH₃ —CH₃ C₁₉H₂₃NO 282.18 282.2 25-26 SR—OCH₃ F C₁₈H₂₀FNO₂ 302.15 302.2 25-27 SR —OCH₃ Cl C₁₈H₂₀ClNO₂ 318.12318.0 25-28 RS/SR —OCH₃ —OCH₃ C₁₉H₂₃NO₃ 314.17 314.2 25-29 RS/SR —CN FC₁₈H₁₇FN₂O 297.13 297.2 25-30 SR/RS —C(O)CH₃ F C₁₉H₂₀FNO₂ 314.15 314.225-31 SR —C(O)CH₃ Cl C₁₉H₂₀ClNO₂ 330.12 330.0 25-32 SR/RS —C(O)CH₃ —CF₃C₂₀H₂₀F₃NO₂ 364.14 364.2 25-33 SR/RS —C(O)CH₃ —OCH₃ C₂₀H₂₃NO₃ 326.17326.2 25-34 SR —C(O)OCH₃ F C₁₉H₂₀FNO₃ 330.14 330.2While all the aforementioned compounds exhibit affinity for both SERTand NET, the compounds listed in the table below exhibit a NET pK_(i)≧8and a SERT K_(i)/NET K_(i) in the range of 0.1-100.

Cmpd. NET pK_(i) SERT K_(i)/NET K_(i) 25-1 9.1 32 25-2 8.2 0.2 25-3 9.10.5 25-4 9.1 5 25-5 8.8 0.1 25-8 8.6 1.3 25-9 9.4 0.4 25-10 9.2 0.125-11 9.2 1.6 Ex. 9-4 9.2 6.3 25-15 8.6 0.2 25-17 8.6 0.2 25-19 9.1 425-20 9.2 0.2 25-21 8.9 0.6 25-22 9.2 0.2 25-23 8.8 0.1 25-24 8.6 0.325-26 8.9 13 25-30 8.5 10 25-34 9 100

Example 26

Following the procedures described in the examples above, andsubstituting the appropriate starting materials and reagents, compounds26-1 to 26-8, having the following formula, were also prepared:

(VI′)

MS m/z: Stereo- [M + H]⁺ Cmpd. chemistry R¹ R² R³ Formula calcd found26-1 RS/SR 2-F —Cl —Cl C₁₇H₁₆Cl₂FNO 340.06 340.0 26-2 RS/SR 3-F —Cl —ClC₁₇H₁₆Cl₂FNO 340.06 340.0 26-3 RS/SR 3-Cl —Cl —Cl C₁₇H₁₆Cl₃NO 356.03356.0 26-4 RS/SR 2-CH₃ —Cl —Cl C₁₈H₁₉Cl₂NO 336.08 336.0 26-5 RS/SR 3-CH₃—Cl —Cl C₁₈H₁₉Cl₂NO 336.08 336.0 26-6 RS/SR 3-OCH₃ —Cl —Cl C₁₈H₁₉Cl₂NO₂352.08 352.0 26-7 RS/SR 3-OCF₃ —Cl —Cl C₁₈H₁₆Cl₂F₃NO₂ 406.05 406.0 26-8SR 3-SO₂CH₃, —Cl F C₁₈H₁₈ClF₂NO₃S 402.07 402.0 5-FWhile all the aforementioned compounds exhibit affinity for both SERTand NET, the compounds listed in the table below exhibit a NET pK_(i)≧8and a SERT K_(i)/NET K_(i) in the range of 0.1-100.

Cmpd. NET pK_(i) SERT K_(i)/NET K_(i) 26-1 8.8 0.1 26-3 8.3 0.1 26-6 8.40.1

Example 27

Following the procedures described in the examples above, andsubstituting the appropriate starting materials and reagents, compounds27-1 to 27-39, having the following formula, were also prepared:

(VII)

MS m/z: Stereo- [M + H]⁺ Cmpd. chemistry R² R⁴ Formula calcd found 27-1RS/SR F F C₁₇H₁₇F₂NO 290.13 290.2 Ex. 7 SR F F C₁₇H₁₇F₂NO 290.13 290.227-2 RS F F C₁₇H₁₇F₂NO 290.13 290.0 27-3 RS/SR F Cl C₁₇H₁₇ClFNO 306.10306.2 27-4 SS F Cl C₁₇H₁₇ClFNO 306.10 306.6 Ex. 15 SR F Cl C₁₇H₁₇ClFNO306.10 306.4 27-5 RS/SR Cl Cl C₁₇H₁₇Cl₂NO 322.07 322.0 27-6 SR Cl ClC₁₇H₁₇Cl₂NO 322.07 322.0 27-7 RS Cl Cl C₁₇H₁₇Cl₂NO 322.07 322.0 27-8 SRCl F C₁₇H₁₇ClFNO 306.10 306.0 27-9 RS Cl F C₁₇H₁₇ClFNO 306.10 306.027-10 SR Cl —CH₃ C₁₈H₂₀ClNO 302.12 302.0 27-11 RS Cl —CH₃ C₁₈H₂₀ClNO302.12 302.0 27-12 RS/SR Cl —NO₂ C₁₇H₁₇ClN₂O₃ 333.09 330.0 27-13 RS/SR—CH₃ F C₁₈H₂₀FNO 286.15 286.2 27-14 SR —CH₃ F C₁₈H₂₀FNO 286.15 286.227-15 RS —CH₃ F C₁₈H₂₀FNO 286.15 286.2 27-16 RS/SR —CH₃ Cl C₁₈H₂₀ClNO302.12 302.2 27-17 SR —CH₃ Cl C₁₈H₂₀ClNO 302.12 302.0 27-18 RS —CH₃ ClC₁₈H₂₀ClNO 302.12 302.0 27-19 SS —CH₃ Cl C₁₈H₂₀ClNO 302.12 302.0 27-20RR —CH₃ Cl C₁₈H₂₀ClNO 302.12 302.0 27-21 RS/SR —CF₃ Cl C₁₈H₁₇ClF₃NO356.10 356.0 27-22 RS/SR —CH₃ —NO₂ C₁₈H₂₀N₂O₃ 313.15 313.2 27-23 SR—CH₂CH₃ F C₁₉H₂₂FNO 300.17 300.4 27-24 RS —CH₂CH₃ F C₁₉H₂₂FNO 300.17300.2 27-25 SR —OCH₃ F C₁₈H₂₀FNO₂ 302.15 302.2 27-26 RS —OCH₃ FC₁₈H₂₀FNO₂ 302.15 302.2 27-27 SR —OCH₃ Cl C₁₈H₂₀ClNO₂ 318.12 318.4 27-28RS —OCH₃ Cl C₁₈H₂₀ClNO₂ 318.12 318.4 27-29 RS/SR —OCH₃ —NO₂ C₁₈H₂₀N₂O₄329.14 329.4 27-30 RS —OCH₃ —NO₂ C₁₈H₂₀N₂O₄ 329.14 329.4 27-31 SR —OCH₃—NO₂ C₁₈H₂₀N₂O₄ 329.14 329.4 27-32 SR/RS —C(O)CH₃ F C₁₉H₂₀FNO₂ 314.15314.2 27-33 RS/SR —NO₂ —CH₃ C₁₈H₂₀N₂O₃ 313.15 313.2 27-34 SR —C(O)OCH₃Cl C₁₉H₂₀ClNO₃ 346.11 346.0 27-35 RS —C(O)OCH₃ Cl C₁₉H₂₀ClNO₃ 346.11346.0 27-36 SR —C(O)OCH₂CH₃ Cl C₂₀H₂₂ClNO₃ 360.13 360.0 27-37 RS—C(O)OCH₂CH₃ Cl C₂₀H₂₂ClNO₃ 360.13 360.0 27-38 SR —C(O)O—CH(CH₃)₂ ClC₂₁H₂₄ClNO₃ 374.14 374.2 27-39 RS —C(O)O—CH(CH₃)₂ Cl C₂₁H₂₄ClNO₃ 374.14374.2While all the aforementioned compounds exhibit affinity for both SERTand NET, the compounds listed in the table below exhibit a NET pK_(i)≧8and a SERT K_(i)/NET K_(i) in the range of 0.1-100.

Cmpd. NET pK_(i) SERT K_(i)/NET K_(i) 27-1 8.1 0.6 Ex. 7 8.5 3.2 27-38.3 0.1 Ex. 15 8.6 0.3 27-5 8.5 0.1 27-6 8.9 0.2 27-8 8.6 1.6 27-10 9.20.8 27-13 8.5 0.3 27-14 8.7 0.3 27-17 8.6 0.1 27-21 8 0.6 27-23 9 0.827-25 9.1 4.6 27-27 9.5 0.4 27-33 8 1.6 27-34 8.6 4 27-36 8.4 0.6

Example 28

Following the procedures described in the examples above, andsubstituting the appropriate starting materials and reagents, compounds28-1 to 28-21, having the following formula, were also prepared:

(VII′)

MS m/z: Stereo- [M + H]⁺ Cmpd. chemistry R¹ R² R⁴ Formula calcd found28-1 SR 2-SO₂—CH₃ F F C₁₈H₁₉F₂NO₃S 368.11 368.0 28-2 SR 4-SO₂—CH₃ F FC₁₈H₁₉F₂NO₃S 368.11 368.0 28-3 SR 3-CN F Cl C₁₈H₁₆ClFN₂O 331.09 331.228-4 SR 4-CN F Cl C₁₈H₁₆ClFN₂O 331.09 331.2 28-5 RS/SR 2-Cl F ClC₁₇H₁₆Cl₂FNO 340.06 340.0 28-6 RS/SR 4-F F Cl C₁₇H₁₆ClF₂NO 324.09 324.028-7 RS/SR 4-Cl F Cl C₁₇H₁₆Cl₂FNO 340.06 340.0 28-8 SR 4-SO₂—CH₃ F ClC₁₈H₁₉ClFNO₂S 384.08 384.0 28-9 RS/SR 3,5-diF F Cl C₁₇H₁₅ClF₃NO 342.08342.0 28-10 RR/SS 3,5-diF F Cl C₁₇H₁₅ClF₃NO 342.08 342.0 28-11 RS/SR3-F, 5-Cl F Cl C₁₇H₁₅Cl₂F₂NO 358.05 358.0 28-12 RS/SR 3,5-di-CH₃ F ClC₁₉H₂₁ClFNO 334.13 334.0 28-13 RS/SR 3-F, 5-CH₃ F Cl C₁₈H₁₈ClF₂NO 338.10338.0 28-14 SR 3,5-diF —CH₂CH₃ F C₁₉H₂₀F₃NO 336.15 336.0 28-15 RS3,5-diF —CH₂CH₃ F C₁₉H₂₀F₃NO 336.15 336.0 28-16 RR/SS 2-Cl —OCH₃ FC₁₈H₁₉ClFNO₂ 336.11 336.0 28-17 SR 3,5-diF —OCH₃ F C₁₈H₁₈F₃NO₂ 338.13338.0 28-18 RS 3,5-diF —OCH₃ F C₁₈H₁₈F₃NO₂ 338.13 338.0 28-19 SR 3,5-diF—OCH₃ Cl C₁₈H₁₈ClF₂NO₂ 354.10 354.0 28-20 RS/SR 3-Cl —OCH₃ —NO₂C₁₈H₁₉ClN₂O₄ 363.10 363.0 28-21 RS/SR 3—CH₃ OCH₃ —NO₂ C₁₉H₂₂N₂O₄ 343.16343.2While all the aforementioned compounds exhibit affinity for both SERTand NET, the compounds listed in the table below exhibit a NET pK_(i)≧8and a SERT K_(i)/NET K_(i) in the range of 0.1-100.

Cmpd. NET pK_(i) SERT K_(i)/NET K_(i) 28-3 8.2 0.5 28-9 8.5 0.3 28-118.6 0.8 28-13 8.3 0.5 28-14 8.8 3.2 28-17 9.4 25 28-19 9 0.8

Example 29

Following the procedures described in the examples above, andsubstituting the appropriate starting materials and reagents, compounds29-1 to 29-32, having the following formula, were also prepared:

(VIII)

MS m/z: Stereo- [M + H]⁺ Cmpd. chemistry R² R⁵ Formula calcd found 29-1RS/SR F F C₁₇H₁₇F₂NO 290.13 290.2 29-2 SR F F C₁₇H₁₇F₂NO 290.13 290.029-3 RS F F C₁₇H₁₇F₂NO 290.13 290.0 29-4 RS/SR F Cl C₁₇H₁₇ClFNO 306.10306.6 29-5 SR F Cl C₁₇H₁₇ClFNO 306.10 306.0 29-6 RS F Cl C₁₇H₁₇ClFNO306.10 306.0 29-7 RS/SR F Br C₁₇H₁₇BrFNO 350.05 350.0 29-8 RS/SR F —CH₃C₁₈H₂₀FNO 286.15 286.2 29-9 SR F —CH₃ C₁₈H₂₀FNO 286.15 286.2 29-10 RS F—CH₃ C₁₈H₂₀FNO 286.15 286.2 29-11 RS/SR Cl Cl C₁₇H₁₇Cl₂NO 322.07 322.029-12 RS/SR Cl F C₁₇H₁₇ClFNO 306.10 306.2 29-13 RS Cl F C₁₇H₁₇ClFNO306.10 306.0 29-14 SR Cl F C₁₇H₁₇ClFNO 306.10 306.0 29-15 RS/SR —CH₃ FC₁₈H₂₀FNO 286.15 286.2 29-16 SR —CH₃ F C₁₈H₂₀FNO 286.15 286.2 29-17 RS—CH₃ F C₁₈H₂₀FNO 286.15 286.2 29-18 RS/SR —CH₃ Cl C₁₈H₂₀ClNO 302.12302.6 29-19 SR —CH₃ Cl C₁₈H₂₀ClNO 302.12 302.0 29-20 RS —CH₃ ClC₁₈H₂₀ClNO 302.12 302.0 29-21 RS/SR —OCH₃ Cl C₁₈H₂₀ClNO₂ 318.12 318.229-22 SR —OCH₃ Cl C₁₈H₂₀ClNO₂ 318.12 318.0 29-23 RS —OCH₃ Cl C₁₈H₂₀ClNO₂318.12 318.0 29-24 SR —OCH₃ F C₁₈H₂₀FNO₂ 302.15 302.6 29-25 RS —OCH₃ FC₁₈H₂₀FNO₂ 302.15 302.2 29-26 RS/SR —OCH₃ —CH₃ C₁₉H₂₃NO₂ 298.17 298.229-27 SR —OCH₃ —CH₃ C₁₉H₂₃NO₂ 298.17 298.6 29-28 RS —OCH₃ —CH₃ C₁₉H₂₃NO₂298.17 298.6 29-29 RS/SR —CN Cl C₁₈H₁₇ClN₂O 313.10 313.0 29-30 RS/SR—C(O)CH₃ Cl C₁₉H₂₀ClNO₂ 330.12 330.0 29-31 SR —C(O)OCH₃ Cl C₁₉H₂₀ClNO₃346.11 346.0 29-32 RS/SR —C(O)CH₃ —OCH₃ C₂₀H₂₃NO₃ 326.17 326.2While all the aforementioned compounds exhibit affinity for both SERTand NET, the compounds listed in the table below exhibit a NET pK_(i)≧8and a SERT K_(i)/NET K_(i) in the range of 0.1-100.

Cmpd. NET pK_(i) SERT K_(i)/NET K_(i) 29-1 8.7 4 29-2 8.9 32 29-3 8.10.5 29-4 8.9 1.6 29-5 9.3 16 29-6 8.4 0.3 29-7 9.1 1.6 29-8 8.8 3.2 29-98.9 10 29-11 8.4 0.2 29-12 8.8 2 29-13 8 0.2 29-14 9 32 29-15 8.4 1.329-16 8.8 7.9 29-18 8 0.1 29-19 8 0.3 29-21 8.5 1 29-22 8.6 2.5 29-249.0 34 29-25 8.1 0.3 29-27 8 2

Example 30

Following the procedures described in the examples above, andsubstituting the appropriate starting materials and reagents, compounds30-1 to 30-12, having the following formula, were also prepared:

(VIII′)

MS m/z: Stereo- [M + H]⁺ Cmpd. chemistry R¹ R² R⁵ Formula calcd found30-1 RS/SR 3,5-diF F Cl C₁₇H₁₅ClF₃NO 342.08 342.0 30-2 SR 3,5-diF F ClC₁₇H₁₅ClF₃NO 342.08 342.0 30-3 RS/SR 3,5-diF Cl Cl C₁₇H₁₅Cl₂F₂NO 358.05358.0 30-4 SR 3,5-diF Cl Cl C₁₇H₁₅Cl₂F₂NO 358.05 358.0 30-5 SR 3,5-diF—OCH₃ F C₁₈H₁₈F₃NO₂ 338.13 338.0 30-6 RS 3,5-diF —OCH₃ F C₁₈H₁₈F₃NO₂338.13 338.0 30-7 RS/SR 2-F —OCH₃ Cl C₁₈H₁₉ClFNO₂ 336.11 336.0 30-8RS/SR 3-F —OCH₃ Cl C₁₈H₁₉ClFNO₂ 336.11 336.0 30-9 RS/SR 3-Cl —OCH₃ ClC₁₈H₁₉Cl₂NO₂ 352.08 352.0 30-10 RS/SR 3-CH₃ —OCH₃ Cl C₁₉H₂₂ClNO₂ 332.13332.2 30-11 RS/SR 3-OCH₃ —OCH₃ Cl C₁₉H₂₂ClNO₃ 348.13 348.2 30-12 RS/SR3-OCF₃ —OCH₃ Cl C₁₉H₁₉ClF₃NO₃ 402.10 402.0While all the aforementioned compounds exhibit affinity for both SERTand NET, the compounds listed in the table below exhibit a NET pK_(i)≧8and a SERT K_(i)/NET K_(i) in the range of 0.1-100.

Cmpd. NET pK_(i) SERT K_(i)/NET K_(i) 30-1 8.9 3.2 30-2 9.1 25 30-3 8.40.3 30-4 8.5 2.5 30-5 9.3 79 30-6 8.3 0.4 30-9 8.1 0.6

Example 31

Following the procedures described in the examples above, andsubstituting the appropriate starting materials and reagents, compounds31-1 to 31-17, having the following formula, were also prepared:

(IX)

MS m/z: Stereo- [M + H]⁺ Cmpd. chemistry R² R⁶ Formula calcd found 31-1RS/SR F F C₁₇H₁₇F₂NO 290.13 290.0 31-2 SR F F C₁₇H₁₇F₂NO 290.13 290.031-3 RS F F C₁₇H₁₇F₂NO 290.13 290.0 31-4 SR F Cl C₁₇H₁₇ClFNO 306.10306.0 31-5 RS F Cl C₁₇H₁₇ClFNO 306.10 306.0 31-6 RS F —CH₃ C₁₈H₂₀FNO286.15 286.2 31-7 SR F —CH₃ C₁₈H₂₀FNO 286.15 286.4 31-8 RS/SR Cl ClC₁₇H₁₇Cl₂NO 322.07 322.0 31-9 RS Cl Cl C₁₇H₁₇Cl₂NO 322.07 322.0 31-10 SRCl Cl C₁₇H₁₇Cl₂NO 322.07 322.4 31-11 RS/SR —CH₃ Cl C₁₈H₂₀ClNO 302.12302.2 31-12 SR —CH₃ Cl C₁₈H₂₀ClNO 302.12 302.0 31-13 RS —CH₃ ClC₁₈H₂₀ClNO 302.12 302.0 31-14 RS/SR —CH₃ —CH₂CH₃ C₂₀H₂₅NO 296.19 296.231-15 RS —OCH₃ F C₁₈H₂₀FNO₂ 302.15 302.2 31-16 SR —OCH₃ F C₁₈H₂₀FNO₂302.15 302.2 31-17 SR —C(O)OCH₃ Cl C₁₉H₂₀ClNO₃ 346.11 346.0While all the aforementioned compounds exhibit affinity for both SERTand NET, the compounds listed in the table below exhibit a NET pK_(i)≧8and a SERT K_(i)/NET K_(i) in the range of 0.1-100.

Cmpd. NET pK_(i) SERT K_(i)/NET K_(i) 31-1 9.1 20 31-2 9.4 79 31-3 8.31.6 31-4 9.9 40 31-5 9.2 1.3 31-6 8.8 2 31-7 9.7 5 31-8 9.3 7.9 31-9 8.92 31-10 9.5 16 31-11 8.7 1.3 31-12 9 1.6 31-13 8 0.6 31-15 8.7 2 31-169.7 79 31-17 8.5 25

Example 32

Following the procedures described in the examples above, andsubstituting the appropriate starting materials and reagents, compounds32-1 to 32-27, having the following formula, were also prepared:

(IX′)

MS m/z: Stereo- [M + H]⁺ Cmpd. chemistry R¹ R² R⁶ Formula calcd found32-1 SR 3,5-diF F Cl C₁₇H₁₅ClF₃NO 342.08 342.0 32-2 RS 3,5-diF F ClC₁₇H₁₅ClF₃NO 342.08 342.2 32-3 SR/RS 2-Cl F —OCH₃ C₁₈H₁₉ClFNO₂ 336.11336.0 32-4 SS/RR 2-Cl F —OCH₃ C₁₈H₁₉ClFNO₂ 336.11 336.0 32-5 RS 3,5-diFF —OCH₃ C₁₈H₁₈F₃NO₂ 338.13 338.0 32-6 RS/SR 2-F Cl Cl C₁₇H₁₆Cl₂FNO340.06 340.0 32-7 RS/SR 2-Cl Cl Cl C₁₇H₁₆Cl₃NO 356.03 356.0 32-8 RR/SS2-Cl Cl Cl C₁₇H₁₆Cl₃NO 356.03 356.0 32-9 RS/SR 3-Cl Cl Cl C₁₇H₁₆Cl₃NO356.03 356.0 32-10 RS/SR 4-Cl Cl Cl C₁₇H₁₆Cl₃NO 356.03 356.0 32-11 RS/SR4-F Cl Cl C₁₇H₁₆Cl₂FNO 340.06 340.0 32-12 RS/SR 3-CH₃ Cl Cl C₁₈H₁₉Cl₂NO336.08 336.0 32-13 RS/SR 3-OCH₃ Cl Cl C₁₈H₁₉Cl₂NO₂ 352.08 352.0 32-14RS/SR 3-OCF₃ Cl Cl C₁₈H₁₆Cl₂F₃NO₂ 406.05 406.0 32-15 SR 3-CN Cl ClC₁₈H₁₆Cl₂N₂O 347.06 346.6 32-16 SR 4-CN Cl Cl C₁₈H₁₆Cl₂N₂O 347.06 346.432-17 SR 3-C(O)NH₂ Cl Cl C₁₈H₁₈Cl₂N₂O₂ 365.07 365.4 32-18 SR 4-C(O)NH₂Cl Cl C₁₈H₁₈Cl₂N₂O₂ 365.07 365.2 32-19 SR 2-SO₂CH₃ Cl Cl C₁₈H₁₉Cl₂NO₃S400.05 400.0 32-20 SR 4-SO₂CH₃ Cl Cl C₁₈H₁₉Cl₂NO₃S 400.05 400.0 32-21RS/SR 3-F, 5-CH₃ Cl Cl C₁₈H₁₈Cl₂FNO 354.08 354.0 32-22 RR/SS 3-F, 5-CH₃Cl Cl C₁₈H₁₈Cl₂FNO 354.08 354.0 32-23 RS/SR 3-F, 5-Cl Cl Cl C₁₇H₁₅Cl₃FNO374.02 374.0 32-24 RS/SR 3,5-diF Cl Cl C₁₇H₁₅Cl₂F₂NO 358.05 358.0 32-25SR 3,5-diF Cl Cl C₁₇H₁₅Cl₂F₂NO 358.05 358.0 32-26 RR/SS 3,5-diF Cl ClC₁₇H₁₅Cl₂F₂NO 358.05 358.0 32-27 RS 3,5-diF Cl Cl C₁₇H₁₅Cl₂F₂NO 358.05358.0While all the aforementioned compounds exhibit affinity for both SERTand NET, the compounds listed in the table below exhibit a NET pK_(i)≧8and a SERT K_(i)/NET K_(i) in the range of 0.1-100.

Cmpd. NET pK_(i) SERT K_(i)/NET K_(i) 32-1 9.8 50 32-2 9.4 2.5 32-3 9.24 32-5 8.7 1.6 32-7 8.4 0.6 32-9 8.2 1.3 32-10 8.7 1.6 32-11 9.1 4 32-128.3 2 32-13 8 0.3 32-15 9 13 32-16 8.8 1 32-17 8.7 2 32-18 8.1 1.3 32-218.9 1 32-22 8 1.6 32-23 9.2 3.2 32-24 9.4 7.9 32-25 9.7 25 32-26 8.2 132-27 8.9 2.5

Example 33

Following the procedures described in the examples above, andsubstituting the appropriate starting materials and reagents, compounds33-1 to 33-12, having the following formula, were also prepared:

(X)

MS m/z: Stereo- [M + H]⁺ Cmpd. chemistry R³ R⁴ Formula calcd found 33-1RS/SR F F C₁₇H₁₇F₂NO 290.13 290.2 33-2 RS/SR F —CH₃ C₁₈H₂₀FNO 286.15286.2 33-3 SR F —CH₃ C₁₈H₂₀FNO 286.15 286.2 33-4 RS F —CH₃ C₁₈H₂₀FNO286.15 286.2 33-5 RS/SR F Cl C₁₇H₁₇ClFNO 306.10 306.0 33-6 SR Cl FC₁₇H₁₇ClFNO 306.10 306.0 33-7 RS Cl F C₁₇H₁₇ClFNO 306.10 306.0 33-8RS/SR Cl Cl C₁₇H₁₇Cl₂NO 322.07 322.0 33-9 RS/SR —CH₃ Cl C₁₈H₂₀ClNO302.12 302.2 33-10 SR —CF₃ F C₁₈H₁₇F₄NO 340.12 340.0 33-11 RS —CF₃ FC₁₈H₁₇F₄NO 340.12 340.0 33-12 RS/SR —OCH₃ —OCH₃ C₁₉H₂₃NO₃ 314.17 314.2While all the aforementioned compounds exhibit affinity for both SERTand NET, the compounds listed in the table below exhibit a NET pK_(i)≧8and a SERT K_(i)/NET K_(i) in the range of 0.1-100.

Cmpd. NET pK_(i) SERT K_(i)/NET K_(i) 33-2 8.3 0.1 33-3 8.3 0.3

Example 34

Following the procedures described in the examples above, andsubstituting the appropriate starting materials and reagents, compounds34-1 to 34-12, having the following formula, were also prepared:

(XI)

MS m/z: Stereo- [M + H]⁺ Cmpd. chemistry R³ R⁵ Formula calcd found 34-1RS/SR F F C₁₇H₁₇F₂NO 290.13 290.2 34-2 SR F F C₁₇H₁₇F₂NO 290.13 290.234-3 RS F F C₁₇H₁₇F₂NO 290.13 290.2 34-4 SR F Cl C₁₇H₁₇ClFNO 306.10306.4 34-5 RS F Cl C₁₇H₁₇ClFNO 306.10 306.0 34-6 SR F —CH₃ C₁₈H₂₀FNO286.15 286.4 34-7 RS F —CH₃ C₁₈H₂₀FNO 286.15 286.2 Ex. 3 RS/SR Cl ClC₁₇H₁₇Cl₂NO 322.07 322.2 34-8 SR Cl Cl C₁₇H₁₇Cl₂NO 322.07 322.4 Ex. 16RS Cl Cl C₁₇H₁₇Cl₂NO 322.07 322.0 34-9 SS Cl Cl C₁₇H₁₇Cl₂NO 322.07 322.034-10 RR Cl Cl C₁₇H₁₇Cl₂NO 322.07 322.0 34-11 RS/SR Cl Br C₁₇H₁₇BrClNO366.02 366.0 34-12 RS/SR —CH₃ —CH₃ C₁₉H₂₃NO 282.18 282.2While all the aforementioned compounds exhibit affinity for both SERTand NET, the compounds listed in the table below exhibit a NET pK_(i)≧8and a SERT K_(i)/NET K_(i) in the range of 0.1-100.

Cmpd. NET pK_(i) SERT K_(i)/NET K_(i) 34-1 8.2 0.5 34-2 8.1 6.3 34-3 8.30.2 34-4 8 0.3 34-5 8.5 0.1 Ex. 3 8.7 0.1 34-8 8.1 0.3 Ex. 16 8.9 0.134-11 8.6 0.1

Example 35

Following the procedures described in the examples above, andsubstituting the appropriate starting materials and reagents, compounds35-1 to 35-20, having the following formula, were also prepared:

(XI′)

Ste- reo- MS m/z: chem- [M + H]⁺ Cmpd. istry R¹ R³ R⁴ Formula calcdfound 35-1 RR/SS 2-Cl F F C₁₇H₁₆ClF₂NO 324.09 324.0 35-2 SR/RS 2-Cl F FC₁₇H₁₆ClF₂NO 324.09 324.0 35-3 RS/SR 2-Cl Cl Cl C₁₇H₁₆Cl₃NO 356.03 356.035-4 RR/SS 2-Cl Cl Cl C₁₇H₁₆Cl₃NO 356.03 356.0 35-5 RS/SR 3-Cl Cl ClC₁₇H₁₆Cl₃NO 356.03 356.0 35-6 RS/SR 4-Cl Cl Cl C₁₇H₁₆Cl₃NO 356.03 356.035-7 RS/SR 2-F Cl Cl C₁₇H₁₆Cl₂FNO 340.06 340.0 35-8 RS/SR 3-F Cl ClC₁₇H₁₆Cl₂FNO 340.06 340.0 35-9 RS/SR 4-F Cl Cl C₁₇H₁₆Cl₂FNO 340.06 340.035-10 RS/SR 2-CH₃ Cl Cl C₁₈H₁₉Cl₂NO 336.08 336.0 35-11 RS/SR 3-CH₃ Cl ClC₁₈H₁₉Cl₂NO 336.08 336.0 35-12 RS/SR 4-CH₃ Cl Cl C₁₈H₁₉Cl₂NO 336.08336.0 35-13 RS/SR 3-OCH₃ Cl Cl C₁₈H₁₉Cl₂NO₂ 352.08 352.0 35-14 RS/SR3,5-diF Cl Cl C₁₇H₁₅Cl₂F₂NO 358.05 358.0 35-15 RR/SS 3,5-diF Cl ClC₁₇H₁₅Cl₂F₂NO 358.05 358.0 35-16 SR 3,5-diF Cl Cl C₁₇H₁₅Cl₂F₂NO 358.05358.0 35-17 RS 3,5-diF Cl Cl C₁₇H₁₅Cl₂F₂NO 358.05 358.0 35-18 RS/SR 3-F,Cl Cl C₁₇H₁₅Cl₃FNO 374.02 374.0 5-Cl 35-19 RS/SR 3-F, Cl Cl C₁₈H₁₈Cl₂FNO354.08 354.0 5-CH₃ 35-20 RR/SS 3-F, Cl Cl C₁₈H₁₈Cl₂FNO 354.08 354.05-CH₃While all the aforementioned compounds exhibit affinity for both SERTand NET, the compounds listed in the table below exhibit a NET pK_(i)≧8and a SERT K_(i)/NET K_(i) in the range of 0.1-100.

Cmpd. NET pK_(i) SERT K_(i)/NET K_(i) 35-3 8.5 0.1 35-9 8.1 0.1 35-128.1 0.1 35-14 8.7 0.3 35-16 8 0.5 35-17 8.8 0.2 35-18 8.3 0.5 35-19 8.20.4

Example 36

Following the procedures described in the examples above, andsubstituting the appropriate starting materials and reagents, compounds36-1 to 36-11 having the following formula, were also prepared:

(XII)

MS m/z: Stereo- [M + H]⁺ Cmpd. chemistry R² R³ R⁴ Formula calcd found36-1 SR F F F C₁₇H₁₆F₃NO 308.12 308.0 36-2 RS F F F C₁₇H₁₆F₃NO 308.12308.0 36-3 SR F F Cl C₁₇H₁₆ClF₂NO 324.09 324.0 36-4 SR F Cl ClC₁₇H₁₆Cl₂FNO 340.06 340.0 36-5 SR F F —CH₃ C₁₈H₁₉F₂NO 304.14 304.4 36-6RS F F —CH₃ C₁₈H₁₉F₂NO 304.14 304.4 36-7 SR F —CH₃ F C₁₈H₁₉F₂NO 304.14304.2 36-8 RS F —CH₃ F C₁₈H₁₉F₂NO 304.14 304.2 36-9 SR F —OCH₃ FC₁₈H₁₉F₂NO₂ 320.14 320.2 36-10 SR Cl F Cl C₁₇H₁₆Cl₂FNO 340.06 340.036-11 SR —C(O)—CH₃ Cl Cl C₁₉H₁₉Cl₂NO₂ 364.08 364.0While all the aforementioned compounds exhibit affinity for both SERTand NET, the compounds listed in the table below exhibit a NET pK_(i)≧8and a SERT K_(i)/NET K_(i) in the range of 0.1-100.

Cmpd. NET pK_(i) SERT K_(i)/NET K_(i) 36-1 8.2 0.8 36-3 8.2 0.1 36-5 8.90.5 36-10 8.5 0.1 36-7 8.3 0.3

Example 37

Following the procedures described in the examples above, andsubstituting the appropriate starting materials and reagents, compounds37-1 and 37-4, having the following formula, were also prepared:

(XII′)

Ste- reo- MS m/z: chem- [M + H]⁺ Cmpd. istry R¹ R² R³ R⁴ Formula calcdfound 37-1 SR 3,5- F F F C₁₇H₁₄F₅NO 344.10 344.0 di-F 37-2 RS 3,5- F F FC₁₇H₁₄F₅NO 344.10 344.0 di-F 37-3 SR/RS 2-Cl F F F C₁₇H₁₅ClF₃NO 342.08342.0 37-4 RR/SS 2-Cl F F F C₁₇H₁₅ClF₃NO 342.08 342.0While all the aforementioned compounds exhibit affinity for both SERTand NET, the compound listed in the table below exhibits a NET pK_(i)≧8and a SERT K_(i)/NET K_(i) in the range of 0.1-100.

Cmpd. NET pK_(i) SERT K_(i)/NET K_(i) 37-1 8.3 4

Example 38

Following the procedures described in the examples above, andsubstituting the appropriate starting materials and reagents, compounds38-1 to 38-18, having the following formula, were also prepared:

(XIII)

MS m/z: Stereo- [M + H]⁺ Cmpd. chemistry R² R³ R⁵ Formula calcd found38-1 RS F F F C₁₇H₁₆F₃NO 308.12 308.0 38-2 SR F F F C₁₇H₁₆F₃NO 308.12308.0 38-3 SR F Cl —CF₃ C₁₈H₁₆ClF₄NO 374.09 374.0 38-4 RS F Cl —CF₃C₁₈H₁₆ClF₄NO 374.09 374.0 38-5 RS/SR Cl Cl Cl C₁₇H₁₆Cl₃NO 356.03 356.038-6 RS Cl Cl Cl C₁₇H₁₆Cl₃NO 356.03 356.4 38-7 SR Cl Cl Cl C₁₇H₁₆Cl₃NO356.03 356.4 38-8 SS Cl Cl Cl C₁₇H₁₆Cl₃NO 356.03 356.4 38-9 RR Cl Cl ClC₁₇H₁₆Cl₃NO 356.03 356.4 38-10 SR Cl F Cl C₁₇H₁₆Cl₂FNO 340.06 340.238-11 RS Cl F Cl C₁₇H₁₆Cl₂FNO 340.06 340.1 Ex. 8-1 SR Cl F FC₁₇H₁₆ClF₂NO 324.09 324.4 Ex. 8-2 RS Cl F F C₁₇H₁₆ClF₂NO 324.09 324.638-12 SR —OCH₃ F F C₁₈H₁₉F₂NO₂ 320.14 319.6 38-13 RS —OCH₃ F FC₁₈H₁₉F₂NO₂ 320.14 319.6 38-14 SR —OCH₃ F Cl C₁₈H₁₉ClFNO₂ 336.11 336.838-15 RS —OCH₃ F Cl C₁₈H₁₉ClFNO₂ 336.11 336.8 38-16 SR —OCH₃ Cl FC₁₈H₁₉ClFNO₂ 336.11 336.8 38-17 RS —OCH₃ Cl F C₁₈H₁₉ClFNO₂ 336.11 336.838-18 SR —C(O)—CH₃ F F C₁₉H₁₉F₂NO₂ 332.14 332.2While all the aforementioned compounds exhibit affinity for both SERTand NET, the compounds listed in the table below exhibit a NET pK_(i)≧8and a SERT K_(i)/NET K_(i) in the range of 0.1-100.

Cmpd. NET pK_(i) SERT K_(i)/NET K_(i) 38-1 8.3 0.2 38-2 8.8 10 38-5 8.70.1 38-6 8.7 0.1 38-7 8.4 0.2 38-10 8.1 0.5 Ex. 8-1 8.7 2.5 38-12 8.3 5

Example 39

Following the procedures described in the examples above, andsubstituting the appropriate starting materials and reagents, compounds39-1 to 39-7, having the following formula, were also prepared:

(XIII′)

Ste- reo- MS m/z: chem- [M + H]⁺ Cmpd. istry R¹ R² R³ R⁵ Formula calcdfound 39-1 RR/SS 2- F F F C₁₇H₁₅ClF₃NO 342.08 342.0 Cl 39-2 SR/RS 2- F FF C₁₇H₁₅ClF₃NO 342.08 342.0 Cl 39-3 RS 3, F F F C₁₇H₁₄F₅NO 344.10 344.05- di- F 39-4 RS/SR 2- Cl Cl Cl C₁₇H₁₅Cl₄NO 389.99 390.0 Cl 39-5 RS/SR3, Cl Cl Cl C₁₇H₁₄Cl₃F₂NO 392.01 392.4 5- di- F 39-6 SR 3, Cl Cl ClC₁₇H₁₄Cl₃F₂NO 392.01 392.0 5- di- F 39-7 RS/SR 4- Cl Cl Cl C₁₇H₁₅Cl₄NO389.99 390.6 ClWhile all the aforementioned compounds exhibit affinity for both SERTand NET, the compounds listed in the table below exhibit a NET pK_(i)≧8and a SERT K_(i)/NET K_(i) in the range of 0.1-100.

Cmpd. NET pK_(i) SERT K_(i)/NET K_(i) 39-2 8.2 0.6 39-3 8.2 0.4 39-4 8.40.1 39-5 8.5 0.2

Example 40

Following the procedures described in the examples above, andsubstituting the appropriate starting materials and reagents, compounds40-1 to 40-37, having the following formula, were also prepared:

(XIV)

MS m/z: Stereo- [M + H]⁺ Cmpd. chemistry R² R³ R⁶ Formula calcd found40-1 RS F F F C₁₇H₁₆F₃NO 308.12 308.6 40-2 RS/SR F F F C₁₇H₁₆F₃NO 308.12308.6 40-3 SR F F F C₁₇H₁₆F₃NO 308.12 308.6 40-4 SR F —OCH₃ FC₁₈H₁₉F₂NO₂ 320.14 320.2 40-5 RS F —OCH₃ F C₁₈H₁₉F₂NO₂ 320.14 320.2 40-6SR F —OCH₃ Cl C₁₈H₁₉ClFNO₂ 336.11 336.0 40-7 SR F F —OCH₃ C₁₈H₁₉F₂NO₂320.14 320.0 40-8 RS F F —OCH₃ C₁₈H₁₉F₂NO₂ 320.14 319.8 40-9 RS Cl Cl ClC₁₇H₁₆Cl₃NO 356.03 356.4 40-10 RS/SR Cl Cl Cl C₁₇H₁₆Cl₃NO 356.03 356.440-11 SR Cl Cl Cl C₁₇H₁₆Cl₃NO 356.03 356.4 40-12 SR Cl Cl F C₁₇H₁₆Cl₂FNO340.06 340.2 40-13 RS Cl Cl F C₁₇H₁₆Cl₂FNO 340.06 340.2 40-14 RS F Cl FC₁₇H₁₆ClF₂NO 324.09 324.6 40-15 RS/SR F Cl F C₁₇H₁₆ClF₂NO 324.09 324.040-16 SR F Cl F C₁₇H₁₆ClF₂NO 324.09 324.6 40-17 SR F Cl F C₁₇H₁₆Cl₂FNO340.06 340.1 40-18 RS F Cl F C₁₇H₁₆Cl₂FNO 340.06 340.1 40-19 SR Cl F FC₁₇H₁₆ClF₂NO 324.09 324.0 Ex. 14 RS Cl F F C₁₇H₁₆ClF₂NO 324.09 324.040-20 SS Cl F F C₁₇H₁₆ClF₂NO 324.09 324.0 40-21 RR Cl F F C₁₇H₁₆ClF₂NO324.09 324.0 40-22 SR Cl F —OCH₃ C₁₈H₁₉ClFNO₂ 336.11 336.8 40-23 RS Cl F—OCH₃ C₁₈H₁₉ClFNO₂ 336.11 336.8 40-24 RS F —CH₃ F C₁₈H₁₉F₂NO 304.14304.2 40-25 RS/SR F —CH₃ F C₁₈H₁₉F₂NO 304.14 304.0 40-26 SR F —CH₃ FC₁₈H₁₉F₂NO 304.14 304.2 40-27 SR F —CH₃ Cl C₁₈H₁₉ClFNO 320.11 320.040-28 RS F —CH₃ Cl C₁₈H₁₉ClFNO 320.11 320.0 40-29 RS Cl —CH₃ FC₁₈H₁₉ClFNO 320.11 320.0 Ex. 13 SR Cl —CH₃ F C₁₈H₁₉ClFNO 320.11 319.840-30 RR Cl —CH₃ F C₁₈H₁₉ClFNO 320.11 320.0 40-31 RS Cl —CH₃ ClC₁₈H₁₉Cl₂NO 336.08 337.2 40-32 RS/SR Cl —CH₃ Cl C₁₈H₁₉Cl₂NO 336.08 336.040-33 SR Cl —CH₃ Cl C₁₈H₁₉Cl₂NO 336.08 337.0 40-34 SS Cl —CH₃ ClC₁₈H₁₉Cl₂NO 336.08 337.0 40-35 SR Cl —OCH₃ F C₁₈H₁₉ClFNO₂ 336.11 336.040-36 SR —C(O)—CH₃ Cl —CH₃ C₂₀H₂₂ClNO₂ 344.13 344.2 40-37 SR —C(O)—OCH₃Cl Cl C₁₉H₁₉Cl₂NO₃ 380.07 380.0While all the aforementioned compounds exhibit affinity for both SERTand NET, the compounds listed in the table below exhibit a NET pK_(i)≧8and a SERT K_(i)/NET K_(i) in the range of 0.1-100.

Cmpd. NET pK_(i) SERT K_(i)/NET K_(i) 40-1 8.7 0.8 40-2 9.3 5 40-3 9.663 40-4 9.2 6.3 40-6 9 5 40-8 9.0 1 40-9 9.4 0.4 40-10 9.5 0.5 40-11 9.51 40-12 9.6 1.3 40-13 9.7 0.3 40-14 9.3 0.4 40-15 9.6 1.3 40-16 9.8 1040-17 9.5 3.2 40-18 9.3 0.5 40-19 9.7 6.3 Ex. 14 9.5 0.4 40-20 8.5 0.140-21 8.4 0.2 40-22 9.2 13 40-23 8.5 0.1 40-24 8.8 0.4 40-25 9.3 2 40-269.6 20 40-27 9.6 5 40-28 9.1 0.4 40-29 9.7 0.4 Ex. 13 9.6 1.3 40-30 8.30.1 40-31 9.1 0.6 40-32 9.3 1 40-33 9.5 3.2 40-34 8 0.1 40-35 9.4 0.3

Example 41

Following the procedures described in the examples above, andsubstituting the appropriate starting materials and reagents, compounds41-1 to 41-39, having the following formula, were also prepared:

(XIV′)

MS m/z: Stereo- [M + H]⁺ Cmpd. chemistry R¹ R² R³ R⁶ Formula calcd found41-1 SR 3,5-diF F F F C₁₇H₁₄F₅NO 344.10 344.0 41-2 RS 3,5-diF F F FC₁₇H₁₄F₅NO 344.10 344.0 41-3 SR 3,5-diF F F —OCH₃ C₁₈H₁₇F₄NO₂ 356.12355.3 41-4 RS 3,5-diF F F —OCH₃ C₁₈H₁₇F₄NO₂ 356.12 356.0 41-5 SR 3,5-diFF Cl F C₁₇H₁₄ClF₄NO 360.07 360.0 41-6 RS 3,5-diF F Cl F C₁₇H₁₄ClF₄NO360.07 360.0 41-7 RS 3,5-diF F —CH₃ F C₁₈H₁₇F₄NO 340.12 340.2 41-8 SR3,5-diF F —CH₃ Cl C₁₈H₁₇ClF₃NO 356.10 356.0 41-9 RS 3,5-diF F —CH₃ ClC₁₈H₁₇ClF₃NO 356.10 356.0 41-10 RS/SR 2-Cl Cl Cl Cl C₁₇H₁₅Cl₄NO 389.99390.8 41-11 RS/SR 3,5-diF Cl Cl Cl C₁₇H₁₄Cl₃F₂NO 392.01 392.4 41-12 RS3,5-diF Cl Cl Cl C₁₇H₁₄Cl₃F₂NO 392.01 392.0 41-13 SR 3,5-diF Cl Cl ClC₁₇H₁₄Cl₃F₂NO 392.01 392.0 41-14 SR 3-CN Cl —CH₃ Cl C₁₉H₁₈Cl₂N₂O 361.08361.4 41-15 SR 4-CN Cl —CH₃ Cl C₁₉H₁₈Cl₂N₂O 361.08 361.4 41-16 SR3-CH₂OH Cl —CH₃ Cl C₁₉H₂₁Cl₂NO₂ 366.10 366.2 41-17 SS 3-CH₂OH Cl —CH₃ ClC₁₉H₂₁Cl₂NO₂ 366.10 366.2 41-18 RS/SR 2-Cl Cl —CH₃ Cl C₁₈H₁₈Cl₃NO 370.05370.0 41-19 RS/SR 4-Cl Cl —CH₃ Cl C₁₈H₁₈Cl₃NO 370.05 370.0 41-20 SR2-SO₂CH₃ Cl —CH₃ Cl C₁₉H₂₁Cl₂NO₃S 414.06 414.0 41-21 SR 4-SO₂CH₃ Cl —CH₃Cl C₁₉H₂₁Cl₂NO₃S 414.06 414.0 41-22 RR/SS 3-F, 5-CH₃ Cl —CH₃ ClC₁₉H₂₀Cl₂FNO 368.09 368.0 41-23 RS/SR 3-F, 5-CH₃ Cl —CH₃ Cl C₁₉H₂₀Cl₂FNO368.09 368.0 41-24 RS/SR 3-F,5-Cl Cl —CH₃ Cl C₁₈H₁₇Cl₃FNO 388.04 388.041-25 RR/SS 3,5-diF Cl —CH₃ Cl C₁₈H₁₇Cl₂F₂NO 372.07 372.0 41-26 RS/SR3,5-diF Cl —CH₃ Cl C₁₈H₁₇Cl₂F₂NO 372.07 372.0 41-27 SR 3,5-diF Cl —CH₃Cl C₁₈H₁₇Cl₂F₂NO 372.07 372.0 41-28 SR 3,5-diF Cl —CH₃ F C₁₈H₁₇ClF₃NO356.10 356.0 41-29 RS 3,5-diF Cl —CH₃ F C₁₈H₁₇ClF₃NO 356.10 356.0 41-30SR 3,5-diF Cl F F C₁₇H₁₄ClF₄NO 360.07 360.0 41-31 RS 3,5-diF Cl F FC₁₇H₁₄ClF₄NO 360.07 360.0 41-32 SR 3-CN Cl F F C₁₈H₁₅ClF₂N₂O 349.08349.0 41-33 RS 3-CN Cl F F C₁₈H₁₅ClF₂N₂O 349.08 349.2 41-34 RR 3-CN Cl FF C₁₈H₁₅ClF₂N₂O 349.08 349.0 41-35 SS 3-CN Cl F F C₁₈H₁₅ClF₂N₂O 349.08349.0 41-36 SR 3-C(O)—NH₂ Cl F F C₁₈H₁₇ClF₂N₂O₂ 367.09 367.2 41-37 SS3-C(O)—NH₂ Cl F F C₁₈H₁₇ClF₂N₂O₂ 367.09 367.2 41-38 RS 3-C(O)—NH₂ Cl F FC₁₈H₁₇ClF₂N₂O₂ 367.09 367.2 41-39 RR 3-C(O)—NH₂ Cl F F C₁₈H₁₇ClF₂N₂O₂367.09 367.2While all the aforementioned compounds exhibit affinity for both SERTand NET, the compounds listed in the table below exhibit a NET pK_(i)≧8and a SERT K_(i)/NET K_(i) in the range of 0.1-100.

Cmpd. NET pK_(i) SERT K_(i)/NET K_(i) 41-1 9.6 100 41-2 8.6 1 41-4 9 141-5 9.7 50 41-6 9.3 1 41-7 9 1.3 41-8 9.4 7.9 41-9 9.1 0.8 41-10 8.80.2 41-11 9.4 0.8 41-12 9.2 0.3 41-13 9.4 2 41-14 9.2 7.9 41-15 9 0.641-17 9 5 41-18 8.8 0.4 41-19 8.9 0.6 41-22 8 0.3 41-23 8.8 0.5 41-24 91 41-25 8.2 0.2 41-26 9.3 1.3 41-27 9.1 0.8 41-28 9.5 6.3 41-29 9.6 0.541-30 9.7 32 41-31 9.6 0.6 41-32 9.4 40 41-33 9.1 0.4 41-34 8.1 0.841-36 9 7.9 41-38 8 0.1

Example 42

Following the procedures described in the examples above, andsubstituting the appropriate starting materials and reagents, compounds42-1 to 42-10, having the following formula, were also prepared:

(XV)

MS m/z: Stereo- [M + H]⁺ Cmpd. chemistry R² R⁴ R⁵ Formula calcd found42-1 SR F F F C₁₇H₁₆F₃NO 308.12 308.0 42-2 RS F F F C₁₇H₁₆F₃NO 308.12308.0 42-3 SR Cl Cl Cl C₁₇H₁₆Cl₃NO 356.03 356.1 42-4 SR Cl —CH₃ FC₁₈H₁₉ClFNO 320.11 320.2 42-5 RS Cl —CH₃ F C₁₈H₁₉ClFNO 320.11 320.1 42-6SR Cl —CH₃ —CH₃ C₁₉H₂₂ClNO 316.14 316.4 42-7 RS Cl —CH₃ —CH₃ C₁₉H₂₂ClNO316.14 316.2 42-8 SR —OCH₃ Cl F C₁₈H₁₉ClFNO₂ 336.11 336.8 42-9 RS —OCH₃Cl F C₁₈H₁₉ClFNO₂ 336.11 336.8 42-10 SR —C(O)CH₃ —CH₃ Cl C₂₀H₂₂ClNO₂344.13 344.2While all the aforementioned compounds exhibit affinity for both SERTand NET, the compounds listed in the table below exhibit a NET pK_(i)≧8and a SERT K_(i)/NET K_(i) in the range of 0.1-100.

Cmpd. NET pK_(i) SERT K_(i)/NET K_(i) 42-1 8.1 1.6 42-4 8.6 0.5 42-8 8.90.4

Example 43

Following the procedures described in the examples above, andsubstituting the appropriate starting materials and reagents, compounds43-1 and 43-2, having the following formula, were also prepared:

(XV′)

MS m/z: Stereo- [M + H]⁺ Cmpd. chemistry R¹ R² R⁴ R⁵ Formula calcd found43-1 SR 3,5-diF F F F C₁₇H₁₄F₅NO 344.10 344.0 43-2 SR 3,5-diF —OCH₃ Cl FC₁₈H₁₇ClF₃NO₂ 372.09 372.0While all the aforementioned compounds exhibit affinity for both SERTand NET, the compounds listed in the table below exhibit a NET pK_(i)≧8and a SERT K_(i)/NET K_(i) in the range of 0.1-100.

Cmpd. NET pK_(i) SERT K_(i)/NET K_(i) 43-1 8.7 32 43-2 8.7 1.3

Example 44

Following the procedures described in the examples above, andsubstituting the appropriate starting materials and reagents, compounds44-1 to 44-29, having the following formula, were also prepared:

(XVI)

MS m/z: Stereo- [M + H]⁺ Cmpd. chemistry R² R⁴ R⁶ Formula calcd found44-1 RS F F F C₁₇H₁₆F₃NO 308.12 308.0 Ex. 12 SR F F F C₁₇H₁₆F₃NO 308.12308.0 44-2 SS F F F C₁₇H₁₆F₃NO 308.12 308.0 44-3 RR F F F C₁₇H₁₆F₃NO308.12 308.0 44-4 SR —CH₂CH₃ F F C₁₉H₂₁F₂NO 318.16 318.0 44-5 RS —CH₂CH₃F F C₁₉H₂₁F₂NO 318.16 318.0 44-6 SR —C(O)CH₃ F F C₁₉H₁₉F₂NO₂ 332.14332.4 44-7 RS —C(O)CH₃ F F C₁₉H₁₉F₂NO₂ 332.14 332.6 44-8 RS/SR F Cl FC₁₇H₁₆ClF₂NO 324.09 324.4 44-9 SR F Cl F C₁₇H₁₆ClF₂NO 324.09 324.0 44-10RS F Cl F C₁₇H₁₆ClF₂NO 324.09 324.0 44-11 SR F —OCH₃ F C₁₈H₁₉F₂NO₂320.14 320.2 44-12 RS F —OCH₃ F C₁₈H₁₉F₂NO₂ 320.14 320.2 44-13 RS/SR FCl Br C₁₇H₁₆BrClFNO 384.01 384.0 44-14 RS/SR Cl Cl Cl C₁₇H₁₆Cl₃NO 356.03356.0 44-15 SR F Cl Cl C₁₇H₁₆Cl₂FNO 340.06 340.2 44-16 RS F Cl ClC₁₇H₁₆Cl₂FNO 340.06 340.3 44-17 SR Cl Cl —CH₃ C₁₈H₁₉Cl₂NO 336.08 336.444-18 RS Cl Cl —CH₃ C₁₈H₁₉Cl₂NO 336.08 336.4 44-19 RR/SS Cl F ClC₁₇H₁₆Cl₂FNO 340.06 340.2 44-20 RS/SR Cl F Cl C₁₇H₁₆Cl₂FNO 340.06 340.244-21 SR Cl F Cl C₁₇H₁₆Cl₂FNO 340.06 340.0 44-22 RS Cl F Cl C₁₇H₁₆Cl₂FNO340.06 340.0 44-23 SR Cl —CH₃ Cl C₁₈H₁₉Cl₂NO 336.08 336.4 44-24 RS Cl—CH₃ Cl C₁₈H₁₉Cl₂NO 336.08 336.4 44-25 RS/SR Br F Br C₁₇H₁₆Br₂FNO 427.96428.0 44-26 RS/SR —CH₃ Cl Cl C₁₈H₁₉Cl₂NO 336.08 336.0 44-27 RS/SR —CH₃—CH₃ —CH₃ C₂₀H₂₅NO 296.19 296.2 44-28 SR —C(O)—OCH₃ F F C₁₉H₁₉F₂NO₃348.13 348.2 44-29 RS —C(O)—OCH₃ F F C₁₉H₁₉F₂NO₃ 348.13 348.0While all the aforementioned compounds exhibit affinity for both SERTand NET, the compounds listed in the table below exhibit a NET pK_(i)≧8and a SERT K_(i)/NET K_(i) in the range of 0.1-100.

Cmpd. NET pK_(i) SERT K_(i)/NET K_(i) Ex. 14 8.7 4 44-4 9.2 0.3 44-6 8.813 44-8 8.4 0.1 44-9 8.6 0.1 44-15 9.1 0.2 44-21 8.2 0.5 44-28 9 2.5

Example 45

Following the procedures described in the examples above, andsubstituting the appropriate starting materials and reagents, compounds45-1 to 45-11, having the following formula, were also prepared:

(XVI′)

MS m/z: Stereo- [M + H]⁺ Cmpd. chemistry R¹ R² R⁴ R⁶ Formula calcd found45-1 SR 3,5-diF F F F C₁₇H₁₄F₅NO 344.10 344.0 45-2 RS 3,5-diF F F FC₁₇H₁₄F₅NO 344.10 344.0 45-3 SR 3-CN F F F C₁₈H₁₅F₃N₂O 333.11 333.2 45-4SR 4-CN F F F C₁₈H₁₅F₃N₂O 333.11 333.2 45-5 SR 3-C(O)—NH₂ F F FC₁₈H₁₇F₃N₂O₂ 351.12 351.6 45-6 SR 4-C(O)—NH₂ F F F C₁₈H₁₇F₃N₂O₂ 351.12351.6 45-7 SR 4-SO₂CH₃ F F F C₁₈H₁₈F₃NO₃S 386.10 386.2 45-8 RS/SR 2-Cl FCl F C₁₇H₁₅Cl₂F₂NO 358.05 358.0 45-9 RS/SR 2-Cl Cl F Cl C₁₇H₁₅Cl₃FNO374.02 373.6 45-10 SR 3,5-diF Cl —CH₃ Cl C₁₈H₁₇Cl₂F₂NO 372.07 372.045-11 RS 3,5-diF Cl —CH₃ Cl C₁₈H₁₇Cl₂F₂NO 372.07 372.0While all the aforementioned compounds exhibit affinity for both SERTand NET, the compounds listed in the table below exhibit a NET pK_(i)≧8and a SERT K_(i)/NET K_(i) in the range of 0.1-100.

Cmpd. NET pK_(i) SERT K_(i)/NET K_(i) 45-1 8.4 7.9 45-3 8 3.2 45-5 8.13.2

Example 46

Following the procedures described in the examples above, andsubstituting the appropriate starting materials and reagents, compounds46-1 to 46-5, having the following formula, were also prepared:

(XVII)

MS m/z: Stereo- [M + H]⁺ Cmpd. chemistry R³ R⁴ R⁵ Formula calcd found46-1 SR F F F C₁₇H₁₆F₃NO 308.12 308.0 46-2 RS F F F C₁₇H₁₆F₃NO 308.12308.0 46-3 SR —CH₃ Cl —CH₃ C₁₉H₂₂ClNO 316.14 316.0 46-4 RS —CH₃ Cl —CH₃C₁₉H₂₂ClNO 316.14 316.2 46-5 RS F —OCH₃ F C₁₈H₁₉F₂NO₂ 320.14 320.2The aforementioned compounds exhibit affinity for both SERT and NET.

Example 47

Following the procedures described in the examples above, andsubstituting the appropriate starting materials and reagents, compounds47-1 to 47-7, having the following formula, were also prepared:

(XX)

MS m/z: Stereo- [M + H]⁺ Cmpd. chemistry R² R³ R⁵ R⁶ Formula calcd found47-1 RS/SR F F F F C₁₇H₁₅F₄NO 326.11 326.0 47-2 SR F F F F C₁₇H₁₅F₄NO326.11 326.0 47-3 RS F F F F C₁₇H₁₅F₄NO 326.11 326.0 47-4 SS F F F FC₁₇H₁₅F₄NO 326.11 326.0 47-5 RR F F F F C₁₇H₁₅F₄NO 326.11 326.0 47-6 SRCl F F F C₁₇H₁₅ClF₃NO 342.08 342.4 47-7 RS Cl F F F C₁₇H₁₅ClF₃NO 342.08342.2 Ex. 10-1 RS/SR Cl F F Cl C₁₇H₁₅Cl₂F₂NO 358.05 358.0 Ex. 11 SR Cl FF Cl C₁₇H₁₅Cl₂F₂NO 358.05 358.2 47-8 SS Cl F F Cl C₁₇H₁₅Cl₂F₂NO 358.05358.0 47-9 RR Cl F F Cl C₁₇H₁₅Cl₂F₂NO 358.05 358.0 47-10 RS Cl F F ClC₁₇H₁₅Cl₂F₂NO 358.05 358.2 Ex. 10-2 RS/SR Cl Cl Cl Cl C₁₇H₁₅Cl₄NO 389.99390.0 47-11 RS/SR —CH₃ —CH₃ —CH₃ —CH₃ C₂₁H₂₇NO 310.21 310.2While all the aforementioned compounds exhibit affinity for both SERTand NET, the compounds listed in the table below exhibit a NET pK_(i)≧8and a SERT K_(i)/NET K_(i) in the range of 0.1-100.

Cmpd. NET pK_(i) SERT K_(i)/NET K_(i) 47-1 9.2 4 47-2 9.4 40 47-3 8.8 147-4 8.2 0.5 47-6 9.4 6.3 47-7 9.3 0.4 Ex. 10-1 9.2 1.3 Ex. 11 9.4 3.247-8 8.2 0.2 47-10 9.2 0.5 Ex. 10-2 8.9 0.1

Example 48

Following the procedures described in the examples above, andsubstituting the appropriate starting materials and reagents, compounds48-1 to 48-12, having the following formula, were also prepared:

(XX′)

MS m/z: Stereo- [M + H]⁺ Cmpd. chemistry R¹ R² R³ R⁵ R⁶ Formula calcdfound 48-1 RS/SR 3,5-diF Cl F F Cl C₁₇H₁₃Cl₂F₄NO 394.03 394.0 48-2 SR3,5-diF Cl F F Cl C₁₇H₁₃Cl₂F₄NO 394.03 394.0 48-3 RS 3,5-diF Cl F F ClC₁₇H₁₃Cl₂F₄NO 394.03 394.0 48-4 RS/SR 2-Cl Cl F F Cl C₁₇H₁₄Cl₃F₂NO392.01 392.0 48-5 SS 3-COOH Cl F F Cl C₁₈H₁₅Cl₂F₂NO₃ 402.04 402.4 48-6SS 3-CHO Cl F F Cl C₁₈H₁₅Cl₂F₂NO₂ 386.04 386.2 48-7 SS 3-C(O)—OCH₃ Cl FF Cl C₁₉H₁₇Cl₂F₂NO₃ 416.06 416.2 48-8 SS 3-C(O)—O—CH₂CH₃ Cl F F ClC₂₀H₁₉Cl₂F₂NO₃ 430.07 430.1 48-9 SS 3-CH₂—NH(CH₂CH₃) Cl F F ClC₂₀H₂₂Cl₂F₂N₂O 415.11 415.0 48-10 SS 3-CH₂—N(CH₃)(CH₂—CH₃) Cl F F ClC₂₁H₂₄Cl₂F₂N₂O 429.12 429.0 48-11 SS 3-C(O)—NHCH₂CH₃ Cl F F ClC₂₀H₂₀Cl₂F₂N₂O₂ 429.09 429.2 48-12 SS 3-C(O)—N(CH₃)CH₂CH₃ Cl F F ClC₂₁H₂₂Cl₂F₂N₂O₂ 443.10 443.2While all the aforementioned compounds exhibit affinity for both SERTand NET, the compounds listed in the table below exhibit a NET pK_(i)≧8and a SERT K_(i)/NET K_(i) in the range of 0.1-100.

Cmpd. NET pK_(i) SERT K_(i)/NET K_(i) 48-1 9.3 2 48-2 9.4 10 48-3 9.6 248-4 8.1 0.2

Example 49

Following the procedures described in the examples above, andsubstituting the appropriate starting materials and reagents, compounds49-1 and 49-8, having the following formula, were also prepared:

(XXI)

MS m/z: Stereo- [M + H]⁺ Cmpd. chemistry R² R³ R⁴ R⁵ R⁶ Formula calcdfound 49-1 SR F F F F F C₁₇H₁₄F₅NO 344.10 344.0 49-2 RS F F F F FC₁₇H₁₄F₅NO 344.10 344.0 49-3 SR F F —CF₃ F F C₁₈H₁₄F₇NO 394.10 394.049-4 RS F F —CF₃ F F C₁₈H₁₄F₇NO 394.10 394.0 49-5 RS F F Cl F FC₁₇H₁₄ClF₄NO 360.07 360.0 49-6 SR Cl F Cl F Cl C₁₇H₁₄Cl₃F₂NO 392.01392.0 49-7 SR —C(O)—CH₃ F F F F C₁₉H₁₇F₄NO₂ 368.12 368.0 49-8 SR—C(O)—OCH₃ F F F F C₁₉H₁₇F₄NO₃ 384.11 384.0While all the aforementioned compounds exhibit affinity for both SERTand NET, the compounds listed in the table below exhibit a NET pK_(i)≧8and a SERT K_(i)/NET K_(i) in the range of 0.1-100.

Cmpd. NET pK_(i) SERT K_(i)/NET K_(i) 49-1 8.4 2.5 49-2 8 0.2 49-8 8.50.4

While the present invention has been described with reference tospecific aspects or embodiments thereof, it will be understood by thoseof ordinary skilled in the art that various changes can be made orequivalents can be substituted without departing from the true spiritand scope of the invention. Additionally, to the extent permitted byapplicable patent statues and regulations, all publications, patents andpatent applications cited herein are hereby incorporated by reference intheir entirety to the same extent as if each document had beenindividually incorporated by reference herein.

1. A compound of formula I:

where: a is 0 to 5; each R¹ is independently selected from halo,—C₁₋₆alkyl, —C₂₋₆alkynyl, —O—C₁₋₆alkyl, —C₁₋₄alkylene-O—C₁₋₄alkyl,—C₀₋₁alkylene-phenyl, —O—C₀₋₃alkylene-phenyl, —C₀₋₆alkylene-OH, —CN,—C₀₋₂alkylene-COOH, —CHO, —C(O)—C₁₋₆alkyl, —C(O)O—C₁₋₄alkyl, —CH₂SH,—S—C₁₋₆alkyl, —C₁₋₄alkylene-S—C₁₋₄alkyl, —SO₂—C₁₋₆alkyl,—SO₂NR^(a)R^(b), —NHSO₂R^(a), —C₀₋₁alkylene-NR^(a)R^(b),—NHC(O)—C₁₋₆alkyl, —C(O)NR^(a)R^(b), and —NO₂; R² through R⁶ areindependently selected from H, halo, —C₁₋₆alkyl, —C₂₋₆alkynyl,—O—C₁₋₆alkyl, —C₁₋₄alkylene-O—C₁₋₄alkyl, —C₀₋₁alkylene-phenyl,—O—C₀₋₃alkylene-phenyl, —C₀₋₆alkylene-OH, —CN, —C₀₋₂alkylene-COOH, —CHO,—C(O)—C₁₋₆alkyl, —C(O)O—C₁₋₄alkyl, —CH₂SH, —S—C₁₋₆alkyl,—C₁₋₄alkylene-S—C₁₋₄alkyl, —SO₂—C₁₋₆alkyl, —SO₂NR^(a)R^(b), —NHSO₂R^(a),—C₀₋₁alkylene-NR^(a)R^(b), —NHC(O)—C₁₋₆alkyl, —C(O)NR^(a)R^(b), and—NO₂; R^(a) and R^(b) are independently H or —C₁₋₄alkyl; each alkyl inR¹ through R⁶ is optionally substituted with 1 to 5 fluoro atoms; andeach phenyl in R¹ through R⁶ is optionally substituted with 1 or 2groups independently selected from halo, —C₁₋₆alkyl, and —O—C₁₋₆alkyl;or a pharmaceutically acceptable salt thereof.
 2. The compound of claim1, where a is 0, 1 or
 2. 3. The compound of claim 1, where a is 1; andR¹ is halo, —C₁₋₆alkyl, —O—C₁₋₆alkyl optionally substituted with 1 to 5fluoro atoms, —C₀₋₆alkylene-OH, —CN, —C₀₋₂alkylene-COOH, —CHO,—C(O)O—C₁₋₄alkyl or —C(O)NR^(a)R^(b).
 4. The compound of claim 1, wherea is 2; and each R¹ is independently halo, —C₁₋₆alkyl optionallysubstituted with 1 to 5 fluoro atoms, or —SO₂—C₁₋₆alkyl.
 5. The compoundof claim 1, where R² is: H; halo; —C₁₋₆alkyl optionally substituted with1 to 3 fluoro atoms; —O—C₁₋₆alkyl optionally substituted with 1 to 3fluoro atoms; —C₀₋₁alkylene-phenyl optionally substituted with 1 to 2halo atoms; —O—C₀₋₃alkylene-phenyl; —C₀₋₆alkylene-OH; —CN;—C(O)—C₁₋₆alkyl; —C(O)O—C₁₋₄alkyl; —S—C₁₋₆alkyl; —SO₂—C₁₋₆alkyl; or—NO₂.
 6. The compound of claim 1, where R³ is: H; halo; —C₁₋₆alkyloptionally substituted with 1 to 3 fluoro atoms; —O—C₁₋₆alkyl optionallysubstituted with 1 to 3 fluoro atoms; —O—C₀₋₃alkylene-phenyl optionallysubstituted with 1 halo, —C₁₋₆alkyl, or —O—C₁₋₆alkyl group; or —NO₂. 7.The compound of claim 1, where R⁴ is: H; halo; —C₁₋₆alkyl optionallysubstituted with 1 to 5 fluoro atoms; —O—C₁₋₆alkyl optionallysubstituted with 1 to 5 fluoro atoms; —C₀₋₁alkylene-phenyl;—O—C₀₋₃alkylene-phenyl; —SO₂—C₁₋₆alkyl; —C(O)NH₂; or —NO₂.
 8. Thecompound of claim 1, where R⁵ is H, halo, or —C₁₋₆alkyl.
 9. The compoundof claim 1, where H, halo, —C₁₋₆alkyl, or —O—C₁₋₆alkyl.
 10. The compoundof claim 1, where R² through R⁶ are H.
 11. The compound of claim 10,where a is 0, or a is 1 and R¹ is halo, —C₁₋₆alkyl, —O—C₁₋₆alkyl,—C₀₋₆alkylene-OH, or —CHO.
 12. The compound of claim 1, where R² is anon-hydrogen moiety, and R³ through R⁶ are H.
 13. The compound of claim12, where: a is 0; and R² is halo, —C₁₋₆alkyl, —O—C₁₋₆alkyl,—C₀₋₁alkylene-phenyl, —O—C₀₋₃alkylene-phenyl, —C₀₋₆alkylene-OH,—C(O)—C₁₋₆alkyl, —C(O)O—C₁₋₄alkyl, —S—C₁₋₆alkyl, —SO₂—C₁₋₆alkyl, or—NO₂; where each alkyl is optionally substituted with 1 to 5 fluoroatoms, and each phenyl is optionally substituted with 1 or 2 groupsindependently selected from halo; or a is 1 or 2; each R¹ isindependently halo, —C₁₋₆alkyl optionally substituted with 1 to 5 fluoroatoms, —O—C₁₋₆alkyl optionally substituted with 1 to 5 fluoro atoms,—C₀₋₆alkylene-OH, —CN, —SO₂—C₁₋₆alkyl, or —C(O)NR^(a)R^(b); and R² ishalo, —C₁₋₆alkyl, —O—C₁₋₆alkyl, or —C₀₋₁alkylene-phenyl.
 14. Thecompound of claim 1, where R³ is a non-hydrogen moiety, and R² and R⁴through R⁶ are H.
 15. The compound of claim 14, where: a is 0; and R³is: halo; —C₁₋₆alkyl optionally substituted with 1 to 5 fluoro atoms;—O—C₁₋₆alkyl optionally substituted with 1 to 5 fluoro atoms;—O—C₀₋₃alkylene-phenyl optionally substituted with a halo, —C₁₋₆alkyl,or —O—C₁₋₆alkyl group; or —NO₂; a is 1; R¹ is halo, —C₁₋₆alkyl, or—O—C₁₋₆alkyl optionally substituted with 1 to 5 fluoro atoms; and R³ ishalo; or a is 2; R¹ is independently halo or —SO₂—C₁₋₆alkyl; and R³ ishalo.
 16. The compound of claim 1, where R⁴ is a non-hydrogen moiety,and R², R³, R⁵, and R⁶ are H.
 17. The compound of claim 16, where: a is0; and R⁴ is: halo; —C₁₋₆alkyl optionally substituted with 1 to 5 fluoroatoms; —O—C₁₋₆alkyl optionally substituted with 1 to 5 fluoro atoms;—C₀₋₁alkylene-phenyl; —O—C₀₋₃alkylene-phenyl; —SO₂—C₁₋₆alkyl; or—C(O)NR^(a)R^(b); or a is 1; R¹ is halo, —C₁₋₆alkyl, or —O—C₁₋₆alkyloptionally substituted with 1 to 5 fluoro atoms; and R⁴ is halo.
 18. Thecompound of claim 1, where R² and R³ are non-hydrogen moieties, and R⁴through R⁶ are H.
 19. The compound of claim 18, where: a is 0; and R² ishalo, —C₁₋₆alkyl, —O—C₁₋₆alkyl, —CN, —C(O)—C₁₋₆alkyl, or—C(O)O—C₁₋₄alkyl; and R³ is halo, —C₁₋₆alkyl optionally substituted with1 to 5 fluoro atoms, —O—C₁₋₆alkyl, or —O—C₀₋₃alkylene-phenyl; a is 1; R¹is halo, —C₁₋₆alkyl, or —O—C₁₋₆alkyl optionally substituted with 1 to 5fluoro atoms; and R² and R³ are independently halo; or a is 2; each R¹is independently halo or —SO₂—C₁₋₆alkyl; and R² and R³ are independentlyhalo.
 20. The compound of claim 1, where R² and R⁴ are non-hydrogenmoieties, and R³, R⁵ and R⁶ are H.
 21. The compound of claim 20, where:a is 0; and R² is halo, —C₁₋₆alkyl optionally substituted with 1 to 5fluoro atoms, —O—C₁₋₆alkyl, —C(O)—C₁₋₆alkyl, or —NO₂; and R⁴ is halo,—C₁₋₆alkyl, or —NO₂; or where a is 1 or 2; each R¹ is independentlyhalo, —C₁₋₆alkyl, —CN, or —SO₂—C₁₋₆alkyl; and R² and R⁴ areindependently halo, —C₁₋₆alkyl, —O—C₁₋₆alkyl, or —NO₂.
 22. The compoundof claim 1, where R² and R⁵ are non-hydrogen moieties, R³, R⁴ and R⁶ areH.
 23. The compound of claim 22, where: a is 0; and R² is halo,—C₁₋₆alkyl, —O—C₁₋₆alkyl, —CN, or —C(O)—C₁₋₆alkyl; and R⁵ is halo,—C₁₋₆alkyl, or —O—C₁₋₆alkyl; or a is 1 or 2; each R¹ is independentlyhalo —C₁₋₆alkyl, or —O—C₁₋₆alkyl, where —O—C₁₋₆alkyl is optionallysubstituted with 1 to 5 fluoro atoms; R² is halo or —O—C₁₋₆alkyl; and R⁵is halo.
 24. The compound of claim 1, where R² and R⁶ are non-hydrogenmoieties and R³, R⁴ and R⁵ are H.
 25. The compound of claim 24, where: ais 0; and R² is halo, —C₁₋₆alkyl, or —O—C₁₋₆alkyl; and R⁶ is halo or—C₁₋₆alkyl; or a is 1 or 2; each R¹ is independently halo, —C₁₋₆alkyl,—O—C₁₋₆alkyl optionally substituted with 1 to 5 fluoro atoms, —CN,—SO₂—C₁₋₆alkyl, or —C(O)NH₂; R² is halo; and R⁶ is halo or —O—C₁₋₆alkyl.26. The compound of claim 1, where R³ and R⁴ are non-hydrogen moieties,and R², R⁵ and R⁶ are H.
 27. The compound of claim 26, where a is 0; R³is halo, —C₁₋₆alkyl optionally substituted with 1 to 5 fluoro atoms, or—O—C₁₋₆alkyl; and R⁴ is halo, —C₁₋₆alkyl, or —O—C₁₋₆alkyl.
 28. Thecompound of claim 1, where R³ and R⁵ are non-hydrogen moieties; and R²,R⁴ and R⁶ are H.
 29. The compound of claim 28, where: a is 0; and R³ andR⁵ are independently halo or —C₁₋₆alkyl; or a is 1 or 2; each R¹ isindependently halo, —C₁₋₆alkyl, or —O—C₁₋₆alkyl; and R³ and R⁵ areindependently halo.
 30. The compound of claim 1, where R², R³, and R⁴are non-hydrogen moieties, and R⁵ and R⁶ are H.
 31. The compound ofclaim 30, where: a is 0; R² is halo or —C(O)—C₁₋₆alkyl; R³ is halo,—C₁₋₆alkyl, or —O—C₁₋₆alkyl; and R⁴ is halo or —C₁₋₆alkyl; or a is 1 or2; and R¹, R², R³, and R⁴ are independently halo.
 32. The compound ofclaim 1, where R², R³, and R⁵ are non-hydrogen moieties, and R⁴ and R⁶are H.
 33. The compound of claim 32, where: a is 0; R² is halo,—O—C₁₋₆alkyl, or —C(O)—C₁₋₆alkyl; R³ is halo; and R⁵ is halo or—C₁₋₆alkyl optionally substituted with 1 to 5 fluoro atoms; or a is 1 or2; and each R¹, R², R³, and R⁵ are independently halo.
 34. The compoundof claim 1, where R², R³, and R⁶ are non-hydrogen moieties; and R⁴ andR⁵ are H.
 35. The compound of claim 34, where: a is 0; R² is halo or—C(O)—C₁₋₆alkyl; R³ is halo, —C₁₋₆alkyl, or —O—C₁₋₆alkyl; and R⁶ ishalo, —C₁₋₆alkyl, or —O—C₁₋₆alkyl; or a is 1 or 2; each R¹ isindependently halo, —C₁₋₆alkyl, —C₀₋₆alkylene-OH, —CN, —SO₂—C₁₋₆alkyl,or —C(O)NH₂; R² is halo; R³ is halo or —C₁₋₆alkyl; and R⁶ is halo or—O—C₁₋₆alkyl.
 36. The compound of claim 1, where R², R⁴, and R⁵ arenon-hydrogen moieties, and R³ and R⁶ are H.
 37. The compound of claim36, where: a is 0; R² is halo, —O—C₁₋₆alkyl, or —C(O)—C₁₋₆alkyl; R⁴ ishalo or —C₁₋₆alkyl; and halo or —C₁₋₆alkyl; or a is 2; each R¹ isindependently halo; and R², R⁴, and R⁵ are independently halo or—O—C₁₋₆alkyl.
 38. The compound of claim 1, where R², R⁴, and R⁶ arenon-hydrogen moieties, and R³ and R⁵ are H.
 39. The compound of claim38, where: a is 0; and R², R⁴, and R⁶ are independently halo,—C₁₋₆alkyl, —O—C₁₋₆alkyl or —C(O)—C₁₋₆alkyl; or a is 1 or 2; each R¹ isindependently halo, —CN, —SO₂—C₁₋₆alkyl, or —C(O)NR^(a)R^(b), whereR^(a) and R^(b) are H; and R², R⁴, and R⁶ are independently halo or—C₁₋₆alkyl.
 40. The compound of claim 1, where R³, R⁴, and R⁵ arenon-hydrogen moieties, and R² and R⁶ are H.
 41. The compound of claim40, where a is 0; and R³ and R⁵ are halo, and R⁴ is —O—C₁₋₆alkyl. 42.The compound of claim 1, where R², R³, R⁴, and R⁵ are non-hydrogenmoieties, and R⁶ is H.
 43. The compound of claim 1, where R², R³, R⁴,and R⁶ are non-hydrogen moieties, and R⁵ is H.
 44. The compound of claim1, where R², R³, R⁵, and R⁶ are non-hydrogen moieties, and R⁴ is H. 45.The compound of claim 44, where: a is 0; and R², R³, R⁵, and R⁶ areindependently halo or —C₁₋₆alkyl; or a is 1 or 2; each R¹ isindependently halo, —C₀₋₂alkylene-COOH, —CHO, —C(O)O—C₁₋₄alkyl,—C₀₋₁alkylene-NR^(a)R^(b), or —C(O)NR^(a)R^(b); and R², R³, R⁵, and R⁶are independently halo.
 46. The compound of claim 1, where R², R³, R⁴,R⁵, and R⁶ are non-hydrogen moieties.
 47. The compound of claim 46,where a is 0; R² is halo, —C(O)—C₁₋₆alkyl, or —C(O)O—C₁₋₄alkyl; R³, R⁵,and R⁶ are independently halo; and R⁴ is halo or —C₁₋₆alkyl optionallysubstituted with 1 to 5 fluoro atoms.
 48. The compound of claim 1, whichhas a configuration selected from:

or is enriched in a stereoisomeric form having said configuration. 49.An intermediate useful in the synthesis of the compound of claim 1,having the formula:

where P represents an amino-protecting group.
 50. A method of preparingthe compound of claim 1, the process comprising deprotecting a compoundof the formula:

where P represents an amino-protecting group, to provide a compound offormula I or a salt thereof.
 51. A pharmaceutical composition comprisingthe compound of claim 1 and a pharmaceutically acceptable carrier. 52.The pharmaceutical composition of claim 51 further comprising a secondtherapeutic agent selected from anti-Alzheimer's agents,anticonvulsants, antidepressants, anti-Parkinson's agents, dualserotonin-norepinephrine reuptake inhibitors, non-steroidalanti-inflammatory agents, norepinephrine reuptake inhibitors, opioidagonists, selective serotonin reuptake inhibitors, sodium channelblockers, sympatholytics, and combinations thereof.
 53. A method oftreating a patient that is suffering from a disease or disorder that istreated by the inhibition of the serotonin and/or the norepinephrinetransporter, comprising administering a therapeutically effective amountof the compound of claim 1, wherein the disease or disorder is selectedfrom a pain disorder, a depressive disorder, an affective disorder,attention deficit hyperactivity disorder, a cognitive disorder, stressurinary incontinence, chronic fatigue syndrome, obesity, and vasomotorsymptoms associated with menopause.
 54. The method of claim 53, whereinthe pain disorder is neuropathic pain or fibromyalgia.